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Han Y, Gudmundsdottir B, Gudmundsson KO, Roy KR, Tisdale J, Du Y. MLL1 complex is a critical regulator of fetal hemoglobin repression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.24.645036. [PMID: 40196665 PMCID: PMC11974897 DOI: 10.1101/2025.03.24.645036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Increasing fetal-type hemoglobin (HbF) expression in adult erythroid cells holds promise in the treatment of sickle cell disease (SCD) and β-thalassemia. We have identified MLL1 complex as a critical regulator of fetal and embryonic hemoglobin repression. Knockdowns of MEN1 and KMT2A, encoding essential components of the complex, caused a significant downregulation of BCL11A expression and a substantial increase in γ- and ε-globin mRNA levels in HUDEP-2 cells. Significant binding of MEN1 and KMT2A were readily detected at the promoter and a critical enhancer of BCL11A in HUDEP-2 cells, suggesting that BCL11A is a direct transcriptional target of MLL1 complex. Consistent with these results, MEN1 or KMT2A knockdown in normal human CD34 + hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation also significantly decreased their BCL11A expression and increased their γ- and ε-globin expression and the production of F cells in the culture. Treatment of these cells with MENIN inhibitors yielded similar results and promoted erythroid differentiation with minimal effects on their growth. These findings underscore a critical role of MLL1 complex in regulating fetal and embryonic hemoglobin expression and suggest that MENIN inhibitors could offer a promising therapeutic approach for sickle cell disease and β-thalassemia.
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Hommel K, Kauth AMA, Kirupakaran A, Theisen S, Hayduk M, Niemeyer FC, Beuck C, Zadmard R, Bayer P, Jan Ravoo B, Voskuhl J, Schrader T, Knauer SK. Functional Linkers Support Targeting of Multivalent Tweezers to Taspase1. Chemistry 2024; 30:e202401542. [PMID: 38958349 DOI: 10.1002/chem.202401542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 07/01/2024] [Accepted: 07/02/2024] [Indexed: 07/04/2024]
Abstract
Taspase 1 is a unique protease not only pivotal for embryonic development but also implicated in leukemias and solid tumors. As such, this enzyme is a promising while still challenging therapeutic target, and with its protein structure featuring a flexible loop preceding the active site a versatile model system for drug development. Supramolecular ligands provide a promising complementary approach to traditional small-molecule inhibitors. Recently, the multivalent arrangement of molecular tweezers allowed the successful targeting of Taspase 1's surface loop. With this study we now want to take the next logic step und utilize functional linker systems that not only allow the implementation of novel properties but also engage in protein surface binding. Consequently, we chose two different linker types differing from the original divalent assembly: a backbone with aggregation-induced emission (AIE) properties to enable monitoring of binding and a calix[4]arene scaffold initially pre-positioning the supramolecular binding units. With a series of four AIE-equipped ligands with stepwise increased valency we demonstrated that the functionalized AIE linkers approach ligand binding affinities in the nanomolar range and allow efficient proteolytic inhibition of Taspase 1. Moreover, implementation of the calix[4]arene backbone further enhanced the ligands' inhibitory potential, pointing to a specific linker contribution.
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Affiliation(s)
- Katrin Hommel
- Molecular Biology II, Center of Medical Biotechnology (ZMB) and Center for Nanointegration (CENIDE), University of Duisburg-Essen, Universitätsstrasse 5, 45141, Essen, Germany
| | - Alisa-Maite A Kauth
- Organic Chemistry Institute and Center for Soft Nanoscience, University of Münster, Busso-Peus-Straße 10, 48149, Münster, Germany
| | - Abbna Kirupakaran
- Institute of Organic Chemistry I, Biosupramolecular Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45141, Essen, Germany
| | - Sebastian Theisen
- Institute of Organic Chemistry I, Biosupramolecular Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45141, Essen, Germany
| | - Matthias Hayduk
- Faculty of Chemistry (Organic Chemistry II), Center of Medical Biotechnology (ZMB) and Center for Nanointegration (CENIDE), University of Duisburg-Essen, Universitätsstrasse 7, 45117, Essen, Germany
| | - Felix C Niemeyer
- Institute of Organic Chemistry I, Biosupramolecular Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45141, Essen, Germany
| | - Christine Beuck
- Structural and Medicinal Biochemistry, Center of Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstrasse 5, 45141, Essen, Germany
| | - Reza Zadmard
- Department of Organic Chemistry, Chemistry and Chemical Engineering Research Center of Iran (CCERCI), P. O. Box 14335-186, Tehran, Iran
| | - Peter Bayer
- Structural and Medicinal Biochemistry, Center of Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstrasse 5, 45141, Essen, Germany
| | - Bart Jan Ravoo
- Organic Chemistry Institute and Center for Soft Nanoscience, University of Münster, Busso-Peus-Straße 10, 48149, Münster, Germany
| | - Jens Voskuhl
- Faculty of Chemistry (Organic Chemistry II), Center of Medical Biotechnology (ZMB) and Center for Nanointegration (CENIDE), University of Duisburg-Essen, Universitätsstrasse 7, 45117, Essen, Germany
| | - Thomas Schrader
- Institute of Organic Chemistry I, Biosupramolecular Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45141, Essen, Germany
| | - Shirley K Knauer
- Molecular Biology II, Center of Medical Biotechnology (ZMB) and Center for Nanointegration (CENIDE), University of Duisburg-Essen, Universitätsstrasse 5, 45141, Essen, Germany
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Cuglievan B, Kantarjian H, Rubnitz JE, Cooper TM, Zwaan CM, Pollard JA, DiNardo CD, Kadia TM, Guest E, Short NJ, McCall D, Daver N, Nunez C, Haddad FG, Garcia M, Bhalla KN, Maiti A, Catueno S, Fiskus W, Carter BZ, Gibson A, Roth M, Khazal S, Tewari P, Abbas HA, Bourgeois W, Andreeff M, Shukla NN, Truong DD, Connors J, Ludwig JA, Stutterheim J, Salzer E, Juul-Dam KL, Sasaki K, Mahadeo KM, Tasian SK, Borthakur G, Dickson S, Jain N, Jabbour E, Meshinchi S, Garcia-Manero G, Ravandi F, Stein EM, Kolb EA, Issa GC. Menin inhibitors in pediatric acute leukemia: a comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community. Leukemia 2024; 38:2073-2084. [PMID: 39179671 PMCID: PMC11436367 DOI: 10.1038/s41375-024-02368-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/23/2024] [Accepted: 07/29/2024] [Indexed: 08/26/2024]
Abstract
Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias.
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Affiliation(s)
- Branko Cuglievan
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Hagop Kantarjian
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jeffrey E Rubnitz
- Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Todd M Cooper
- Cancer and Blood Disorders Center, Seattle Children's Hospital, University of Washington, Seattle, WA, USA
| | - C Michel Zwaan
- Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands; Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands; The Innovative Therapies for Children with Cancer Consortium, Paris, France
| | | | - Courtney D DiNardo
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tapan M Kadia
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Erin Guest
- Department of Pediatric Oncology, Children's Mercy, Kansas City, MO, USA
| | - Nicholas J Short
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David McCall
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Naval Daver
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Cesar Nunez
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Fadi G Haddad
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Miriam Garcia
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kapil N Bhalla
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Abhishek Maiti
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Samanta Catueno
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Warren Fiskus
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bing Z Carter
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amber Gibson
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael Roth
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sajad Khazal
- Division of Transplant and Cellular Therapy, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Priti Tewari
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer, Houston, TX, USA
| | - Hussein A Abbas
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Michael Andreeff
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Neerav N Shukla
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Danh D Truong
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jeremy Connors
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer, Houston, TX, USA
| | - Joseph A Ludwig
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Elisabeth Salzer
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Kristian L Juul-Dam
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Koji Sasaki
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kris M Mahadeo
- Division of Pediatric Transplantation and Cellular Therapy, Duke University, Durham, NC, USA
| | - Sarah K Tasian
- Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Gautam Borthakur
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Samantha Dickson
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nitin Jain
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Elias Jabbour
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Soheil Meshinchi
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | | | - Farhad Ravandi
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Eytan M Stein
- Department of Leukemia, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - E Anders Kolb
- Moseley Institute for Cancer and Blood Disorders, Nemours Children's Health, Wilmington, DE, USA
| | - Ghayas C Issa
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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4
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LaRue-Nolan KC, Arul GLR, Sigafoos AN, Shi J, Fernandez-Zapico ME. Insights into the mechanisms driven by H3K4 KMTs in pancreatic cancer. Biochem J 2024; 481:983-997. [PMID: 39078225 PMCID: PMC11332384 DOI: 10.1042/bcj20230374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 07/11/2024] [Accepted: 07/15/2024] [Indexed: 07/31/2024]
Abstract
Pancreatic cancer is a malignancy arising from the endocrine or exocrine compartment of this organ. Tumors from exocrine origin comprise over 90% of all pancreatic cancers diagnosed. Of these, pancreatic ductal adenocarcinoma (PDAC) is the most common histological subtype. The five-year survival rate for PDAC ranged between 5 and 9% for over four decades, and only recently saw a modest increase to ∼12-13%, making this a severe and lethal disease. Like other cancers, PDAC initiation stems from genetic changes. However, therapeutic targeting of PDAC genetic drivers has remained relatively unsuccessful, thus the focus in recent years has expanded to the non-genetic factors underlying the disease pathogenesis. Specifically, it has been proposed that dynamic changes in the epigenetic landscape promote tumor growth and metastasis. Emphasis has been given to the re-organization of enhancers, essential regulatory elements controlling oncogenic gene expression, commonly marked my histone 3 lysine 4 monomethylation (H3K4me1). H3K4me1 is typically deposited by histone lysine methyltransferases (KMTs). While well characterized as oncogenes in other cancer types, recent work has expanded the role of KMTs as tumor suppressor in pancreatic cancer. Here, we review the role and translational significance for PDAC development and therapeutics of KMTs.
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Affiliation(s)
- Kayla C. LaRue-Nolan
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, U.S.A
| | | | - Ashley N. Sigafoos
- Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, MN, U.S.A
| | - Jiaqi Shi
- Department of Pathology and Clinical Labs, Rogel Cancer Center and Center for RNA Biomedicine, University of Michigan, Ann Arbor, MI, U.S.A
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5
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Yang Z, Zhang G, Zhao R, Tian T, Zhi J, Wei G, Roeder RG, Jing L, Yu M. MLL-AF9 regulates transcriptional initiation in mixed lineage leukemic cells. J Biol Chem 2024; 300:107566. [PMID: 39002676 PMCID: PMC11345648 DOI: 10.1016/j.jbc.2024.107566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/15/2024] [Accepted: 07/03/2024] [Indexed: 07/15/2024] Open
Abstract
Mixed lineage leukemia-fusion proteins (MLL-FPs) are believed to maintain gene activation and induce MLL through aberrantly stimulating transcriptional elongation, but the underlying mechanisms are incompletely understood. Here, we show that both MLL1 and AF9, one of the major fusion partners of MLL1, mainly occupy promoters and distal intergenic regions, exhibiting chromatin occupancy patterns resembling that of RNA polymerase II in HEL, a human erythroleukemia cell line without MLL1 rearrangement. MLL1 and AF9 only coregulate over a dozen genes despite of their co-occupancy on thousands of genes. They do not interact with each other, and their chromatin occupancy is also independent of each other. Moreover, AF9 deficiency in HEL cells decreases global TBP occupancy while decreases CDK9 occupancy on a small number of genes, suggesting an accessory role of AF9 in CDK9 recruitment and a possible major role in transcriptional initiation via initiation factor recruitment. Importantly, MLL1 and MLL-AF9 occupy promoters and distal intergenic regions, exhibiting identical chromatin occupancy patterns in MLL cells, and MLL-AF9 deficiency decreased occupancy of TBP and TFIIE on major target genes of MLL-AF9 in iMA9, a murine acute myeloid leukemia cell line inducibly expressing MLL-AF9, suggesting that it can also regulate initiation. These results suggest that there is no difference between MLL1 and MLL-AF9 with respect to location and size of occupancy sites, contrary to what people have believed, and that MLL-AF9 may also regulate transcriptional initiation in addition to widely believed elongation.
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Affiliation(s)
- Zimei Yang
- Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Ge Zhang
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Ruoyu Zhao
- Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Tian Tian
- Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Junhong Zhi
- Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
| | - Gang Wei
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Robert G Roeder
- Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York, USA
| | - Lili Jing
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Ming Yu
- Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
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Liu W, Wu Y, Ma R, Zhu X, Wang R, He L, Shu M. Multi-omics analysis of a case of congenital microtia reveals aldob and oxidative stress associated with microtia etiology. Orphanet J Rare Dis 2024; 19:218. [PMID: 38802922 PMCID: PMC11129396 DOI: 10.1186/s13023-024-03149-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 03/27/2024] [Indexed: 05/29/2024] Open
Abstract
BACKGROUND Microtia is reported to be one of the most common congenital craniofacial malformations. Due to the complex etiology and the ethical barrier of embryonic study, the precise mechanisms of microtia remain unclear. Here we report a rare case of microtia with costal chondrodysplasia based on bioinformatics analysis and further verifications on other sporadic microtia patients. RESULTS One hundred fourteen deleterious insert and deletion (InDel) and 646 deleterious SNPs were screened out by WES, candidate genes were ranked in descending order according to their relative impact with microtia. Label-free proteomic analysis showed that proteins significantly different between the groups were related with oxidative stress and energy metabolism. By real-time PCR and immunohistochemistry, we further verified the candidate genes between other sporadic microtia and normal ear chondrocytes, which showed threonine aspartase, cadherin-13, aldolase B and adiponectin were significantly upregulated in mRNA levels but were significantly lower in protein levels. ROS detection and mitochondrial membrane potential (∆ Ψ m) detection proved that oxidative stress exists in microtia chondrocytes. CONCLUSIONS Our results not only spot new candidate genes by WES and label-free proteomics, but also speculate for the first time that metabolism and oxidative stress may disturb cartilage development and this might become therapeutic targets and potential biomarkers with clinical usefulness in the future.
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Affiliation(s)
- Wenbo Liu
- The First Affiliated Hospital of Xi'an Jiao Tong University, No.277 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Yi Wu
- Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Rulan Ma
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiao Tong University Medical College, Xi'an, Shaanxi, China
| | - Xinxi Zhu
- The First Affiliated Hospital of Xi'an Jiao Tong University, No.277 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Rui Wang
- The First Affiliated Hospital of Xi'an Jiao Tong University, No.277 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Lin He
- The First Affiliated Hospital of Xi'an Jiao Tong University, No.277 Yanta West Road, Xi'an, Shaanxi, 710061, China
| | - Maoguo Shu
- The First Affiliated Hospital of Xi'an Jiao Tong University, No.277 Yanta West Road, Xi'an, Shaanxi, 710061, China.
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7
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Jamali M, Barar E, Shi J. Unveiling the Molecular Landscape of Pancreatic Ductal Adenocarcinoma: Insights into the Role of the COMPASS-like Complex. Int J Mol Sci 2024; 25:5069. [PMID: 38791111 PMCID: PMC11121229 DOI: 10.3390/ijms25105069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/02/2024] [Accepted: 05/04/2024] [Indexed: 05/26/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is poised to become the second leading cause of cancer-related death by 2030, necessitating innovative therapeutic strategies. Genetic and epigenetic alterations, including those involving the COMPASS-like complex genes, have emerged as critical drivers of PDAC progression. This review explores the genetic and epigenetic landscape of PDAC, focusing on the role of the COMPASS-like complex in regulating chromatin accessibility and gene expression. Specifically, we delve into the functions of key components such as KDM6A, KMT2D, KMT2C, KMT2A, and KMT2B, highlighting their significance as potential therapeutic targets. Furthermore, we discuss the implications of these findings for developing novel treatment modalities for PDAC.
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Affiliation(s)
- Marzieh Jamali
- Department of Pathology & Clinical Labs, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Erfaneh Barar
- Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran 1416634793, Iran
| | - Jiaqi Shi
- Department of Pathology & Clinical Labs, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
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8
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Darvishi F, Beiranvand E, Kalhor H, Shahbazi B, Mafakher L. Homology modeling and molecular docking studies to decrease glutamine affinity of Yarrowia lipolytica L-asparaginase. Int J Biol Macromol 2024; 263:130312. [PMID: 38403216 DOI: 10.1016/j.ijbiomac.2024.130312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 01/10/2024] [Accepted: 02/18/2024] [Indexed: 02/27/2024]
Abstract
L-Asparaginase is a key component in the treatment of leukemias and lymphomas. However, the glutamine affinity of this therapeutic enzyme is an off-target activity that causes several side effects. The modeling and molecular docking study of Yarrowia lipolytica L-asparaginase (YL-ASNase) to reduce its l-glutamine affinity and increase its stability was the aim of this study. Protein-ligand interactions of wild-type and different mutants of YL-ASNase against L-asparagine compared to l-glutamine were assessed using AutoDock Vina tools because the crystal structure of YL-ASNase does not exist in the protein data banks. The results showed that three mutants, T171S, T171S-N60A, and T171A-T223A, caused a considerable increase in L-asparagine affinity and a decrease in l-glutamine affinity as compared to the wild-type and other mutants. Then, molecular dynamics simulation and MM/GBSA free energy were applied to assess the stability of protein structure and its interaction with ligands. The three mutated proteins, especially T171S-N60A, had higher stability and interactions with L-asparagine than l-glutamine in comparison with the wild-type. The YL-ASNase mutants could be introduced as appropriate therapeutic candidates that might cause lower side effects. However, the functional properties of these mutated enzymes need to be confirmed by genetic manipulation and in vitro and in vivo studies.
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Affiliation(s)
- Farshad Darvishi
- Department of Microbiology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran; Research Center for Applied Microbiology and Microbial Biotechnology (CAMB), Alzahra University, Tehran, Iran.
| | - Elham Beiranvand
- Department of Microbiology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran.
| | - Hourieh Kalhor
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
| | - Behzad Shahbazi
- School of Pharmacy, Semnan University of Medical Sciences, Semnan, Iran
| | - Ladan Mafakher
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Van HT, Xie G, Dong P, Liu Z, Ge K. KMT2 Family of H3K4 Methyltransferases: Enzymatic Activity-dependent and -independent Functions. J Mol Biol 2024; 436:168453. [PMID: 38266981 PMCID: PMC10957308 DOI: 10.1016/j.jmb.2024.168453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 01/11/2024] [Accepted: 01/17/2024] [Indexed: 01/26/2024]
Abstract
Histone-lysine N-methyltransferase 2 (KMT2) methyltransferases are critical for gene regulation, cell differentiation, animal development, and human diseases. KMT2 biological roles are often attributed to their methyltransferase activities on lysine 4 of histone H3 (H3K4). However, recent data indicate that KMT2 proteins also possess non-enzymatic functions. In this review, we discuss the current understanding of KMT2 family, with a focus on their enzymatic activity-dependent and -independent functions. Six mammalian KMT2 proteins of three subgroups, KMT2A/B (MLL1/2), KMT2C/D (MLL3/4), and KMT2F/G (SETD1A/B or SET1A/B), have shared and distinct protein domains, catalytic substrates, genomic localizations, and associated complex subunits. Recent studies have revealed the importance of KMT2C/D in enhancer regulation, differentiation, development, tumor suppression and highlighted KMT2C/D enzymatic activity-dependent and -independent roles in mouse embryonic development and cell differentiation. Catalytic dependent and independent functions for KMT2A/B and KMT2F/G in gene regulation, differentiation, and development are less understood. Finally, we provide our perspectives and lay out future research directions that may help advance the investigation on enzymatic activity-dependent and -independent biological roles and working mechanisms of KMT2 methyltransferases.
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Affiliation(s)
- Hieu T Van
- Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 50, Room 4149, 50 South Dr, Bethesda, MD 20892, USA.
| | - Guojia Xie
- Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 50, Room 4149, 50 South Dr, Bethesda, MD 20892, USA.
| | - Peng Dong
- Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA.
| | - Zhe Liu
- Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA.
| | - Kai Ge
- Adipocyte Biology and Gene Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 50, Room 4149, 50 South Dr, Bethesda, MD 20892, USA.
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10
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Zhao S, Lu J, Pan B, Fan H, Byrum SD, Xu C, Kim A, Guo Y, Kanchi KL, Gong W, Sun T, Storey AJ, Burkholder NT, Mackintosh SG, Kuhlers PC, Edmondson RD, Strahl BD, Diao Y, Tackett AJ, Raab JR, Cai L, Song J, Wang GG. TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons. Nature 2023; 623:633-642. [PMID: 37938770 PMCID: PMC11000523 DOI: 10.1038/s41586-023-06688-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 09/27/2023] [Indexed: 11/09/2023]
Abstract
Trimethylation of histone H3 lysine 9 (H3K9me3) is crucial for the regulation of gene repression and heterochromatin formation, cell-fate determination and organismal development1. H3K9me3 also provides an essential mechanism for silencing transposable elements1-4. However, previous studies have shown that canonical H3K9me3 readers (for example, HP1 (refs. 5-9) and MPP8 (refs. 10-12)) have limited roles in silencing endogenous retroviruses (ERVs), one of the main transposable element classes in the mammalian genome13. Here we report that trinucleotide-repeat-containing 18 (TNRC18), a poorly understood chromatin regulator, recognizes H3K9me3 to mediate the silencing of ERV class I (ERV1) elements such as LTR12 (ref. 14). Biochemical, biophysical and structural studies identified the carboxy-terminal bromo-adjacent homology (BAH) domain of TNRC18 (TNRC18(BAH)) as an H3K9me3-specific reader. Moreover, the amino-terminal segment of TNRC18 is a platform for the direct recruitment of co-repressors such as HDAC-Sin3-NCoR complexes, thus enforcing optimal repression of the H3K9me3-demarcated ERVs. Point mutagenesis that disrupts the TNRC18(BAH)-mediated H3K9me3 engagement caused neonatal death in mice and, in multiple mammalian cell models, led to derepressed expression of ERVs, which affected the landscape of cis-regulatory elements and, therefore, gene-expression programmes. Collectively, we describe a new H3K9me3-sensing and regulatory pathway that operates to epigenetically silence evolutionarily young ERVs and exert substantial effects on host genome integrity, transcriptomic regulation, immunity and development.
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Affiliation(s)
- Shuai Zhao
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Jiuwei Lu
- Department of Biochemistry, University of California, Riverside, CA, USA
| | - Bo Pan
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
| | - Huitao Fan
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
- The First Affiliated Hospital of Harbin Medical University, Harbin, P. R. China
| | - Stephanie D Byrum
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Chenxi Xu
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Arum Kim
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Yiran Guo
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Krishna L Kanchi
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Weida Gong
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Tongyu Sun
- Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA
| | - Aaron J Storey
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Nathaniel T Burkholder
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Samuel G Mackintosh
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Peyton C Kuhlers
- Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Ricky D Edmondson
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Brian D Strahl
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Yarui Diao
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
- Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA
| | - Alan J Tackett
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Jesse R Raab
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
- Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Ling Cai
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA
- Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Jikui Song
- Department of Biochemistry, University of California, Riverside, CA, USA.
| | - Gang Greg Wang
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA.
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
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11
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Sezer A, Kayhan G, Percin FE. Long-term follow-up and novel variant in Suleiman-El-Hattab syndrome: Expanding the genotypic and clinical spectrum of a rare neurodevelopmental disorder. Eur J Med Genet 2023; 66:104809. [PMID: 37474017 DOI: 10.1016/j.ejmg.2023.104809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 06/04/2023] [Accepted: 07/18/2023] [Indexed: 07/22/2023]
Abstract
Suleiman-El-Hattab syndrome (SULEHS, OMIM #618950) is an autosomal recessive multisystem developmental disorder characterized by distinctive facial appearance, global developmental delay/intellectual disability, poor expressive speech and happy demeanor. SULEHS is an ultra-rare disorder associated with biallelic loss-of-function variants of the TASP1 gene, and up-to-date, seven patients from five families have been reported in the literature. Loss of TASP1 function has been reported to alter H3K4 histone modifications and expression of TFIIA and HOX transcription factors in the SULEHS phenotype. In this report, a new patient molecularly diagnosed with SULEHS by a novel homozygous c.404-2A > G variant in the TASP1 gene is presented with the long-term follow-up. Although the majority of the patient's clinical characteristics were similar to those of previously reported SULEHS patients, this study was the first to describe some additional anomalies, such as cystic hygroma, increased nuchal thickness, coarctation of the aorta, pulmonary stenosis, pulmonary sequestration anomaly, chronic constipation, encephalomalacia, and aggressive behavior. Because of the remarkable similarities between the clinical features of Baraitser-Winter syndrome (BRWS) and the patient, BRWS was considered the most likely diagnosis before the molecular diagnosis. Network analysis also supported that the interaction of the SULEHS-associated TASP1 gene with the BRWS-associated ACTB and ACTG1 genes through common intermediate molecules. Overall, despite the existence of differences in clinical features, inheritance patterns, and underlying pathophysiology between BRWS and SULEHS, both diseases could be considered in the differential diagnosis due to the high clinical similarities, including the dysmorphic features, growth parameters, neurodevelopmental phenotype, neurological problems, and multisystem involvement. Additionally, this report could contribute to a better understanding of the genotypic and clinical features of SULEHS by describing a novel pathogenic variant and new clinical features, such as prenatal manifestations.
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Affiliation(s)
- Abdullah Sezer
- Gazi University, Faculty of Medicine, Department of Medical Genetics, Ankara, Turkey; Dr. Sami Ulus Maternity and Children's Training and Research Hospital, Department of Medical Genetics, Ankara, Turkey
| | - Gulsum Kayhan
- Gazi University, Faculty of Medicine, Department of Medical Genetics, Ankara, Turkey
| | - Ferda E Percin
- Gazi University, Faculty of Medicine, Department of Medical Genetics, Ankara, Turkey.
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12
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Sharma R, Incoronato A, Zhang C, Jayanthan A, Shah R, Narendran A. Establishment of a t(11;19), KMT2A Rearranged B-ALL Cell Line for Preclinical Evaluation and Novel Therapeutics Development for Refractory Infant Leukemia. J Pediatr Hematol Oncol 2023; 45:e750-e756. [PMID: 37494611 DOI: 10.1097/mph.0000000000002697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 05/04/2023] [Indexed: 07/28/2023]
Abstract
Leukemia, diagnosed in children less than 12 months of age, is a rare condition with an aggressive disease presentation and poor response to conventional chemotherapeutic agents. In addition, the unique vulnerability of the affected population does not always permit the use of markedly intense regimens with higher doses of cytotoxic agents. However, the unique biology of these leukemic cells also provides opportunities for the identification of effective and potentially well-tolerated targeted therapeutic strategies. In this report, we describe the establishment and characterization of a cell line from the blasts of an infant diagnosed with refractory B-cell acute lymphoblastic leukemia (ALL) carrying the characteristic histone lysine methyltransferase 2A (KMT2A) gene rearrangement. This cell line consists of rapidly proliferating clones of cells with chemosensitivity patterns previously described for KMT2A rearranged leukemia cells, including relative resistance to glucocorticoids and sensitivity to cytarabine. We also show effective targetability with menin inhibitors, indicating the activity of abnormal KMT2A-related pathways and the potential utility of this cell line in comprehensive drug library screens. Overall, our findings report the establishment and in vitro validation of a cell line for research into key aspects of infant leukemia biology and targeted therapeutics development.
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Affiliation(s)
- Ritul Sharma
- Department of Pediatrics and Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Andrea Incoronato
- Department of Hemato-oncology, Pereira Rossell Hospital, Montevideo, Uruguay
| | - Chunfen Zhang
- Department of Pediatrics and Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | - Ravi Shah
- Department of Pediatrics and Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada
| | - Aru Narendran
- Department of Pediatrics and Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada
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13
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Blatter M, Meylan C, Cléry A, Giambruno R, Nikolaev Y, Heidecker M, Solanki JA, Diaz MO, Gabellini D, Allain FHT. RNA binding induces an allosteric switch in Cyp33 to repress MLL1-mediated transcription. SCIENCE ADVANCES 2023; 9:eadf5330. [PMID: 37075125 PMCID: PMC10115415 DOI: 10.1126/sciadv.adf5330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
Mixed-lineage leukemia 1 (MLL1) is a transcription activator of the HOX family, which binds to specific epigenetic marks on histone H3 through its third plant homeodomain (PHD3) domain. Through an unknown mechanism, MLL1 activity is repressed by cyclophilin 33 (Cyp33), which binds to MLL1 PHD3. We determined solution structures of Cyp33 RNA recognition motif (RRM) free, bound to RNA, to MLL1 PHD3, and to both MLL1 and the histone H3 lysine N6-trimethylated. We found that a conserved α helix, amino-terminal to the RRM domain, adopts three different positions facilitating a cascade of binding events. These conformational changes are triggered by Cyp33 RNA binding and ultimately lead to MLL1 release from the histone mark. Together, our mechanistic findings rationalize how Cyp33 binding to MLL1 can switch chromatin to a transcriptional repressive state triggered by RNA binding as a negative feedback loop.
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Affiliation(s)
- Markus Blatter
- Department of Biology, Institute of Biochemistry, ETH Zurich, 8093 Zurich, Switzerland
- Corresponding author. (F.H.-T.A.); (M.B.)
| | - Charlotte Meylan
- Department of Biology, Institute of Biochemistry, ETH Zurich, 8093 Zurich, Switzerland
| | - Antoine Cléry
- Department of Biology, Institute of Biochemistry, ETH Zurich, 8093 Zurich, Switzerland
| | - Roberto Giambruno
- Gene Expression and Muscular Dystrophy Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Yaroslav Nikolaev
- Department of Biology, Institute of Biochemistry, ETH Zurich, 8093 Zurich, Switzerland
| | - Michel Heidecker
- Department of Biology, Institute of Biochemistry, ETH Zurich, 8093 Zurich, Switzerland
| | - Jessica Arvindbhai Solanki
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University of Chicago Medical Center, University of Chicago, Chicago, IL, USA
| | - Manuel O. Diaz
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University of Chicago Medical Center, University of Chicago, Chicago, IL, USA
| | - Davide Gabellini
- Gene Expression and Muscular Dystrophy Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy
| | - Frédéric H.-T. Allain
- Department of Biology, Institute of Biochemistry, ETH Zurich, 8093 Zurich, Switzerland
- Corresponding author. (F.H.-T.A.); (M.B.)
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14
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Taspase1 Facilitates Topoisomerase IIβ-Mediated DNA Double-Strand Breaks Driving Estrogen-Induced Transcription. Cells 2023; 12:cells12030363. [PMID: 36766705 PMCID: PMC9913075 DOI: 10.3390/cells12030363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/10/2023] [Accepted: 01/11/2023] [Indexed: 01/20/2023] Open
Abstract
The human protease Taspase1 plays a pivotal role in developmental processes and cancerous diseases by processing critical regulators, such as the leukemia proto-oncoprotein MLL. Despite almost two decades of intense research, Taspase1's biology is, however, still poorly understood, and so far its cellular function was not assigned to a superordinate biological pathway or a specific signaling cascade. Our data, gained by methods such as co-immunoprecipitation, LC-MS/MS and Topoisomerase II DNA cleavage assays, now functionally link Taspase1 and hormone-induced, Topoisomerase IIβ-mediated transient DNA double-strand breaks, leading to active transcription. The specific interaction with Topoisomerase IIα enhances the formation of DNA double-strand breaks that are a key prerequisite for stimulus-driven gene transcription. Moreover, Taspase1 alters the H3K4 epigenetic signature upon estrogen-stimulation by cleaving the chromatin-modifying enzyme MLL. As estrogen-driven transcription and MLL-derived epigenetic labelling are reduced upon Taspase1 siRNA-mediated knockdown, we finally characterize Taspase1 as a multifunctional co-activator of estrogen-stimulated transcription.
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15
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Höing A, Struth R, Beuck C, Rafieiolhosseini N, Hoffmann D, Stauber RH, Bayer P, Niemeyer J, Knauer SK. Dual activity inhibition of threonine aspartase 1 by a single bisphosphate ligand. RSC Adv 2022; 12:34176-34184. [PMID: 36545626 PMCID: PMC9709806 DOI: 10.1039/d2ra06019a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 11/23/2022] [Indexed: 12/05/2022] Open
Abstract
Therapy resistance remains a challenge for the clinics. Here, dual-active chemicals that simultaneously inhibit independent functions in disease-relevant proteins are desired though highly challenging. As a model, we here addressed the unique protease threonine aspartase 1, involved in various cancers. We hypothesized that targeting basic residues in its bipartite nuclear localization signal (NLS) by precise bisphosphate ligands inhibits additional steps required for protease activity. We report the bisphosphate anionic bivalent inhibitor 11d, selectively binding to the basic NLS cluster (220KKRR223) with high affinity (K D = 300 nM), thereby disrupting its interaction and function with Importin α (IC50 = 6 μM). Cell-free assays revealed that 11d additionally affected the protease's catalytic substrate trans-cleavage activity. Importantly, functional assays comprehensively demonstrated that 11d inhibited threonine aspartase 1 also in living tumor cells. We demonstrate for the first time that intracellular interference with independent key functions in a disease-relevant protein by an inhibitor binding to a single site is possible.
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Affiliation(s)
- Alexander Höing
- Molecular Biology II, Center of Medical Biotechnology (ZMB)/Center for Nanointegration Duisburg-Essen (CENIDE), University of Duisburg-Essen, Universitätsstrasse 5 45141 Essen Germany
| | - Robin Struth
- Organic Chemistry, Center for Nanointegration Duisburg-Essen (CENIDE), University of Duisburg-Essen, Universitätsstrasse 7 45141 Essen Germany
| | - Christine Beuck
- Structural and Medicinal Biochemistry, Center for Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstrasse 5 45141 Essen Germany
| | - Neda Rafieiolhosseini
- Bioinformatics and Computational Biophysics, Center for Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstrasse 5 45141 Essen Germany
| | - Daniel Hoffmann
- Bioinformatics and Computational Biophysics, Center for Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstrasse 5 45141 Essen Germany
| | - Roland H Stauber
- Molecular and Cellular Oncology/ENT, University Medical Center Mainz (UMM) Langenbeckstrasse 1 55101 Mainz Germany
| | - Peter Bayer
- Structural and Medicinal Biochemistry, Center for Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstrasse 5 45141 Essen Germany
| | - Jochen Niemeyer
- Organic Chemistry, Center for Nanointegration Duisburg-Essen (CENIDE), University of Duisburg-Essen, Universitätsstrasse 7 45141 Essen Germany
| | - Shirley K Knauer
- Molecular Biology II, Center of Medical Biotechnology (ZMB)/Center for Nanointegration Duisburg-Essen (CENIDE), University of Duisburg-Essen, Universitätsstrasse 5 45141 Essen Germany
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16
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Höing A, Kirupakaran A, Beuck C, Pörschke M, Niemeyer FC, Seiler T, Hartmann L, Bayer P, Schrader T, Knauer SK. Recognition of a Flexible Protein Loop in Taspase 1 by Multivalent Supramolecular Tweezers. Biomacromolecules 2022; 23:4504-4518. [PMID: 36200481 DOI: 10.1021/acs.biomac.2c00652] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Many natural proteins contain flexible loops utilizing well-defined complementary surface regions of their interacting partners and usually undergo major structural rearrangements to allow perfect binding. The molecular recognition of such flexible structures is still highly challenging due to the inherent conformational dynamics. Notably, protein-protein interactions are on the other hand characterized by a multivalent display of complementary binding partners to enhance molecular affinity and specificity. Imitating this natural concept, we here report the rational design of advanced multivalent supramolecular tweezers that allow addressing two lysine and arginine clusters on a flexible protein surface loop. The protease Taspase 1, which is involved in cancer development, carries a basic bipartite nuclear localization signal (NLS) and thus interacts with Importin α, a prerequisite for proteolytic activation. Newly established synthesis routes enabled us to covalently fuse several tweezer molecules into multivalent NLS ligands. The resulting bi- up to pentavalent constructs were then systematically compared in comprehensive biochemical assays. In this series, the stepwise increase in valency was robustly reflected by the ligands' gradually enhanced potency to disrupt the interaction of Taspase 1 with Importin α, correlated with both higher binding affinity and inhibition of proteolytic activity.
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Affiliation(s)
- Alexander Höing
- Molecular Biology II, Center of Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstrasse 5, 45141 Essen, Germany
| | - Abbna Kirupakaran
- Institute of Organic Chemistry I, University of Duisburg-Essen, Universitätsstrasse 7, 45141 Essen, Germany
| | - Christine Beuck
- Structural and Medicinal Biochemistry, Center of Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstrasse 5, 45141 Essen, Germany
| | - Marius Pörschke
- Structural and Medicinal Biochemistry, Center of Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstrasse 5, 45141 Essen, Germany
| | - Felix C Niemeyer
- Institute of Organic Chemistry I, University of Duisburg-Essen, Universitätsstrasse 7, 45141 Essen, Germany
| | - Theresa Seiler
- Organic Chemistry and Macromolecular Chemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Laura Hartmann
- Organic Chemistry and Macromolecular Chemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Peter Bayer
- Structural and Medicinal Biochemistry, Center of Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstrasse 5, 45141 Essen, Germany
| | - Thomas Schrader
- Institute of Organic Chemistry I, University of Duisburg-Essen, Universitätsstrasse 7, 45141 Essen, Germany
| | - Shirley K Knauer
- Molecular Biology II, Center of Medical Biotechnology (ZMB), University of Duisburg-Essen, Universitätsstrasse 5, 45141 Essen, Germany
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17
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Poreba E, Lesniewicz K, Durzynska J. Histone-lysine N-methyltransferase 2 (KMT2) complexes - a new perspective. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2022; 790:108443. [PMID: 36154872 DOI: 10.1016/j.mrrev.2022.108443] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 06/25/2022] [Accepted: 09/19/2022] [Indexed: 01/01/2023]
Abstract
Histone H3 Lys4 (H3K4) methylation is catalyzed by the Histone-Lysine N-Methyltransferase 2 (KMT2) protein family, and its members are required for gene expression control. In vertebrates, the KMT2s function in large multisubunit complexes known as COMPASS or COMPASS-like complexes (COMplex of Proteins ASsociated with Set1). The activity of these complexes is critical for proper development, and mutation-induced defects in their functioning have frequently been found in human cancers. Moreover, inherited or de novo mutations in KMT2 genes are among the etiological factors in neurodevelopmental disorders such as Kabuki and Kleefstra syndromes. The canonical role of KMT2s is to catalyze H3K4 methylation, which results in a permissive chromatin environment that drives gene expression. However, current findings described in this review demonstrate that these enzymes can regulate processes that are not dependent on methylation: noncatalytic functions of KMT2s include DNA damage response, cell division, and metabolic activities. Moreover, these enzymes may also methylate non-histone substrates and play a methylation-dependent function in the DNA damage response. In this review, we present an overview of the new, noncanonical activities of KMT2 complexes in a variety of cellular processes. These discoveries may have crucial implications for understanding the functions of these methyltransferases in developmental processes, disease, and epigenome-targeting therapeutic strategies in the future.
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Affiliation(s)
- Elzbieta Poreba
- Department of Genetics, Institute of Experimental Biology, Faculty of Biology, Adam Mickiewicz University, ul. Uniwersytetu Poznańskiego 6, 61-614 Poznań, Poland.
| | - Krzysztof Lesniewicz
- Department of Molecular and Cellular Biology, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, ul. Uniwersytetu Poznańskiego 6, 61-614 Poznań, Poland
| | - Julia Durzynska
- Department of Genetics, Institute of Experimental Biology, Faculty of Biology, Adam Mickiewicz University, ul. Uniwersytetu Poznańskiego 6, 61-614 Poznań, Poland.
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18
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Linhorst A, Lübke T. The Human Ntn-Hydrolase Superfamily: Structure, Functions and Perspectives. Cells 2022; 11:cells11101592. [PMID: 35626629 PMCID: PMC9140057 DOI: 10.3390/cells11101592] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/05/2022] [Accepted: 05/06/2022] [Indexed: 01/27/2023] Open
Abstract
N-terminal nucleophile (Ntn)-hydrolases catalyze the cleavage of amide bonds in a variety of macromolecules, including the peptide bond in proteins, the amide bond in N-linked protein glycosylation, and the amide bond linking a fatty acid to sphingosine in complex sphingolipids. Ntn-hydrolases are all sharing two common hallmarks: Firstly, the enzymes are synthesized as inactive precursors that undergo auto-proteolytic self-activation, which, as a consequence, reveals the active site nucleophile at the newly formed N-terminus. Secondly, all Ntn-hydrolases share a structural consistent αββα-fold, notwithstanding the total lack of amino acid sequence homology. In humans, five subclasses of the Ntn-superfamily have been identified so far, comprising relevant members such as the catalytic active subunits of the proteasome or a number of lysosomal hydrolases, which are often associated with lysosomal storage diseases. This review gives an updated overview on the structural, functional, and (patho-)physiological characteristics of human Ntn-hydrolases, in particular.
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19
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Hensel A, Stahl P, Moews L, König L, Patwardhan R, Höing A, Schulze N, Nalbant P, Stauber RH, Knauer SK. The Taspase1/Myosin1f-axis regulates filopodia dynamics. iScience 2022; 25:104355. [PMID: 35601920 PMCID: PMC9121324 DOI: 10.1016/j.isci.2022.104355] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 03/04/2022] [Accepted: 04/28/2022] [Indexed: 11/15/2022] Open
Abstract
The unique threonine protease Tasp1 impacts not only ordered development and cell proliferation but also pathologies. However, its substrates and the underlying molecular mechanisms remain poorly understood. We demonstrate that the unconventional Myo1f is a Tasp1 substrate and unravel the physiological relevance of this proteolysis. We classify Myo1f as a nucleo-cytoplasmic shuttle protein, allowing its unhindered processing by nuclear Tasp1 and an association with chromatin. Moreover, we show that Myo1f induces filopodia resulting in increased cellular adhesion and migration. Importantly, filopodia formation was antagonized by Tasp1-mediated proteolysis, supported by an inverse correlation between Myo1f concentration and Tasp1 expression level. The Tasp1/Myo1f-axis might be relevant in human hematopoiesis as reduced Tasp1 expression coincided with increased Myo1f concentrations and filopodia in macrophages compared to monocytes and vice versa. In sum, we discovered Tasp1-mediated proteolysis of Myo1f as a mechanism to fine-tune filopodia formation, inter alia relevant for cells of the immune system.
Myosin1f is a nucleo-cytoplasmic shuttle protein temporarily located in the nucleus Myosin1f induces filopodia resulting in increased cellular adhesion and migration The protease Taspase1 cleaves Myosin1f, thereby impairing its function Taspase1 and Myosin1f inversely correlate in immune cell differentiation
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Affiliation(s)
- Astrid Hensel
- Department of Molecular Biology II, Center of Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany
- Corresponding author
| | - Paul Stahl
- Department of Molecular Biology II, Center of Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany
| | - Lisa Moews
- Department of Molecular Biology II, Center of Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany
| | - Lena König
- Department of Molecular Biology II, Center of Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany
| | - Rutuja Patwardhan
- Department of Molecular Cell Biology, Center of Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany
| | - Alexander Höing
- Department of Molecular Biology II, Center of Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany
| | - Nina Schulze
- Imaging Center Campus Essen (ICCE), Center of Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany
| | - Perihan Nalbant
- Department of Molecular Cell Biology, Center of Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany
| | - Roland H. Stauber
- Department of Molecular and Cellular Oncology/ENT, University Mainz Medical Center, 55131 Mainz, Germany
| | - Shirley K. Knauer
- Department of Molecular Biology II, Center of Medical Biotechnology (ZMB), University Duisburg-Essen, 45141 Essen, Germany
- Corresponding author
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20
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Nguyen N, Gudmundsson KO, Soltis AR, Oakley K, Roy KR, Han Y, Gurnari C, Maciejewski JP, Crouch G, Ernst P, Dalgard CL, Du Y. Recruitment of MLL1 complex is essential for SETBP1 to induce myeloid transformation. iScience 2022; 25:103679. [PMID: 35036869 PMCID: PMC8749219 DOI: 10.1016/j.isci.2021.103679] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/26/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
Abnormal activation of SETBP1 due to overexpression or missense mutations occurs frequently in various myeloid neoplasms and associates with poor prognosis. Direct activation of Hoxa9/Hoxa10/Myb transcription by SETBP1 and its missense mutants is essential for their transforming capability; however, the underlying epigenetic mechanisms remain elusive. We found that both SETBP1 and its missense mutant SETBP1(D/N) directly interact with histone methyltransferase MLL1. Using a combination of ChIP-seq and RNA-seq analysis in primary hematopoietic stem and progenitor cells, we uncovered extensive overlap in their genomic occupancy and their cooperation in activating many oncogenic transcription factor genes including Hoxa9/Hoxa10/Myb and a large group of ribosomal protein genes. Genetic ablation of Mll1 as well as treatment with an inhibitor of the MLL1 complex OICR-9429 abrogated Setbp1/Setbp1(D/N)-induced transcriptional activation and transformation. Thus, the MLL1 complex plays a critical role in Setbp1-induced transcriptional activation and transformation and represents a promising target for treating myeloid neoplasms with SETBP1 activation.
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Affiliation(s)
- Nhu Nguyen
- Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Kristbjorn O. Gudmundsson
- Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Anthony R. Soltis
- The American Genome Center (TAGC), Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Kevin Oakley
- Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Kartik R. Roy
- Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Yufen Han
- Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Carmelo Gurnari
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Jaroslaw P. Maciejewski
- Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Gary Crouch
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA
| | - Patricia Ernst
- Department of Pediatrics, Section of Hematology/Oncology/BMT, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA
- Department of Pharmacology, University of Colorado, Denver/Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Clifton L. Dalgard
- The American Genome Center (TAGC), Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
| | - Yang Du
- Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
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21
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Höing A, Zimmermann A, Moews L, Killa M, Heimann M, Hensel A, Voskuhl J, Knauer SK. A Bivalent Supramolecular GCP Ligand Enables Blocking of the Taspase1/Importin α Interaction. ChemMedChem 2022; 17:e202100640. [PMID: 34623765 PMCID: PMC9298320 DOI: 10.1002/cmdc.202100640] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Indexed: 12/12/2022]
Abstract
Taspase1 is a unique protease not only pivotal for embryonic development but also implicated in leukemia as well as solid tumors. As such, it is a promising target in cancer therapy, although only a limited number of Taspase1 inhibitors lacking general applicability are currently available. Here we present a bivalent guanidiniocarbonyl-pyrrole (GCP)-containing supramolecular ligand that is capable of disrupting the essential interaction between Taspase1 and its cognate import receptor Importin α in a concentration-dependent manner in vitro with an IC50 of 35 μM. Here, size of the bivalent vs the monovalent construct as well as its derivation with an aromatic cbz-group arose as critical determinants for efficient interference of 2GC. This was also evident when we investigated the effects in different tumor cell lines, resulting in comparable EC50 values (∼40-70 μM). Of note, in higher concentrations, 2GC also interfered with Taspase1's proteolytic activity. We thus believe to set the stage for a novel class of Taspase1 inhibitors targeting a pivotal protein-protein interaction prerequisite for its cancer-associated proteolytic function.
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Affiliation(s)
- Alexander Höing
- Institute for Molecular Biology IICenter for Medical Biotechnology (ZMB)University of Duisburg-EssenUniversitätsstrasse 545117EssenGermany
| | - Alexander Zimmermann
- Faculty of Chemistry (Organic Chemistry) and CENIDEUniversity of Duisburg EssenUniversitätsstrasse 745141EssenGermany
| | - Lisa Moews
- Institute for Molecular Biology IICenter for Medical Biotechnology (ZMB)University of Duisburg-EssenUniversitätsstrasse 545117EssenGermany
| | - Matthias Killa
- Faculty of Chemistry (Organic Chemistry) and CENIDEUniversity of Duisburg EssenUniversitätsstrasse 745141EssenGermany
| | - Marius Heimann
- Faculty of Chemistry (Organic Chemistry) and CENIDEUniversity of Duisburg EssenUniversitätsstrasse 745141EssenGermany
| | - Astrid Hensel
- Institute for Molecular Biology IICenter for Medical Biotechnology (ZMB)University of Duisburg-EssenUniversitätsstrasse 545117EssenGermany
| | - Jens Voskuhl
- Faculty of Chemistry (Organic Chemistry) and CENIDEUniversity of Duisburg EssenUniversitätsstrasse 745141EssenGermany
| | - Shirley K. Knauer
- Institute for Molecular Biology IICenter for Medical Biotechnology (ZMB)University of Duisburg-EssenUniversitätsstrasse 545117EssenGermany
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22
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Riedhammer KM, Burgemeister AL, Cantagrel V, Amiel J, Siquier-Pernet K, Boddaert N, Hertecant J, Kannouche PL, Pouvelle C, Htun S, Slavotinek AM, Beetz C, Diego-Alvarez D, Kampe K, Fleischer N, Awamleh Z, Weksberg R, Kopajtich R, Meitinger T, Suleiman J, El-Hattab AW. OUP accepted manuscript. Hum Mol Genet 2022; 31:3083-3094. [PMID: 35512351 PMCID: PMC9476618 DOI: 10.1093/hmg/ddac098] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 04/04/2022] [Accepted: 04/23/2022] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND TASP1 encodes an endopeptidase activating histone methyltransferases of the KMT2 family. Homozygous loss-of-function variants in TASP1 have recently been associated with Suleiman-El-Hattab syndrome. We report six individuals with Suleiman-El-Hattab syndrome and provide functional characterization of this novel histone modification disorder in a multi-omics approach. METHODS Chromosomal microarray/exome sequencing in all individuals. Western blotting from fibroblasts in two individuals. RNA sequencing and proteomics from fibroblasts in one individual. Methylome analysis from blood in two individuals. Knock-out of tasp1 orthologue in zebrafish and phenotyping. RESULTS All individuals had biallelic TASP1 loss-of-function variants and a phenotype including developmental delay, multiple congenital anomalies (including cardiovascular and posterior fossa malformations), a distinct facial appearance and happy demeanor. Western blot revealed absence of TASP1. RNA sequencing/proteomics showed HOX gene downregulation (HOXA4, HOXA7, HOXA1 and HOXB2) and dysregulation of transcription factor TFIIA. A distinct methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles could be produced. Zebrafish tasp1 knock-out revealed smaller head size and abnormal cranial cartilage formation in tasp1 crispants. CONCLUSION This work further delineates Suleiman-El-Hattab syndrome, a recognizable neurodevelopmental syndrome. Possible downstream mechanisms of TASP1 deficiency include perturbed HOX gene expression and dysregulated TFIIA complex. Methylation pattern suggests that Suleiman-El-Hattab syndrome can be categorized into the group of histone modification disorders including Wiedemann-Steiner and Kabuki syndrome.
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Affiliation(s)
- Korbinian M Riedhammer
- Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
- Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | | | - Vincent Cantagrel
- Developmental Brain Disorders Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR, 75015 Paris, France
| | - Jeanne Amiel
- Department of Genetics, AP-HP, Necker Enfants Malades Hospital, Université Paris Cité, Imagine Institute, 75015 Paris, France
| | - Karine Siquier-Pernet
- Developmental Brain Disorders Laboratory, Université Paris Cité, Imagine Institute, INSERM UMR, 75015 Paris, France
| | - Nathalie Boddaert
- Département de radiologie pédiatrique, INSERM UMR 1163 and INSERM U1000, AP-HP, Necker Enfants Malades Hospital, 75015 Paris, France
| | - Jozef Hertecant
- Division of Genetics and Metabolics, Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates
| | - Patricia L Kannouche
- CNRS UMR 9019, Université Paris-Saclay, Equipe labellisée Ligue contre le Cancer, Gustave Roussy, 94805 Villejuif, France
| | - Caroline Pouvelle
- CNRS UMR 9019, Université Paris-Saclay, Equipe labellisée Ligue contre le Cancer, Gustave Roussy, 94805 Villejuif, France
| | - Stephanie Htun
- Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Anne M Slavotinek
- Department of Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA 94143, USA
| | | | | | | | | | - Zain Awamleh
- Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
| | - Rosanna Weksberg
- Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
- Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
- Department of Molecular Genetics, Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A1, Canada
| | - Robert Kopajtich
- Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
- Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Thomas Meitinger
- Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, 81675 Munich, Germany
| | - Jehan Suleiman
- Division of Neurology, Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates
- Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ayman W El-Hattab
- To whom correspondence should be addressed at: College of Medicine, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates. Tel: +971 508875123; Fax: +97137131044;
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23
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Closantel is an allosteric inhibitor of human Taspase1. iScience 2021; 24:103524. [PMID: 34934933 DOI: 10.1016/j.isci.2021.103524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/11/2021] [Accepted: 11/23/2021] [Indexed: 11/23/2022] Open
Abstract
Dimerization of Taspase1 activates an intrinsic serine protease function that leads to the catalytic Thr234 residue, which allows to catalyze the consensus sequence Q-3X-2D-1⋅G1X2D3D4, present in Trithorax family members and TFIIA. Noteworthy, Taspase1 performs only a single hydrolytic step on substrate proteins, which makes it impossible to screen for inhibitors in a classical screening approach. Here, we report the development of an HTRF reporter assay that allowed the identification of an inhibitor, Closantel sodium, that inhibits Taspase1 in a noncovalent fashion (IC50 = 1.6 μM). The novel inhibitor interferes with the dimerization step and/or the intrinsic serine protease function of the proenzyme. Of interest, Taspase1 is required to activate the oncogenic functions of the leukemogenic AF4-MLL fusion protein and was shown in several studies to be overexpressed in many solid tumors. Therefore, the inhibitor may be useful for further validation of Taspase1 as a target for cancer therapy.
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24
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Klonou A, Chlamydas S, Piperi C. Structure, Activity and Function of the MLL2 (KMT2B) Protein Lysine Methyltransferase. Life (Basel) 2021; 11:823. [PMID: 34440566 PMCID: PMC8401916 DOI: 10.3390/life11080823] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/08/2021] [Accepted: 08/10/2021] [Indexed: 12/31/2022] Open
Abstract
The Mixed Lineage Leukemia 2 (MLL2) protein, also known as KMT2B, belongs to the family of mammalian histone H3 lysine 4 (H3K4) methyltransferases. It is a large protein of 2715 amino acids, widely expressed in adult human tissues and a paralog of the MLL1 protein. MLL2 contains a characteristic C-terminal SET domain responsible for methyltransferase activity and forms a protein complex with WRAD (WDR5, RbBP5, ASH2L and DPY30), host cell factors 1/2 (HCF 1/2) and Menin. The MLL2 complex is responsible for H3K4 trimethylation (H3K4me3) on specific gene promoters and nearby cis-regulatory sites, regulating bivalent developmental genes as well as stem cell and germinal cell differentiation gene sets. Moreover, MLL2 plays a critical role in development and germ line deletions of Mll2 have been associated with early growth retardation, neural tube defects and apoptosis that leads to embryonic death. It has also been involved in the control of voluntary movement and the pathogenesis of early stage childhood dystonia. Additionally, tumor-promoting functions of MLL2 have been detected in several cancer types, including colorectal, hepatocellular, follicular cancer and gliomas. In this review, we discuss the main structural and functional aspects of the MLL2 methyltransferase with particular emphasis on transcriptional mechanisms, gene regulation and association with diseases.
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Affiliation(s)
- Alexia Klonou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.K.); (S.C.)
| | - Sarantis Chlamydas
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.K.); (S.C.)
- Research and Development Department, Active Motif, Inc., Carlsbad, CA 92008, USA
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.K.); (S.C.)
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25
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TASP1 Promotes Proliferation and Migration in Gastric Cancer via EMT and AKT/P-AKT Pathway. J Immunol Res 2021; 2021:5521325. [PMID: 34012990 PMCID: PMC8105097 DOI: 10.1155/2021/5521325] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/02/2021] [Accepted: 04/12/2021] [Indexed: 12/24/2022] Open
Abstract
Threonine aspartase 1 (TASP1) was reported to function in the development of cancer. However, the regulatory mechanism of TASP1 in gastric cancer (GC) remains unclear. In this study, we determined the expression of TASP1 in tissues of GC patients, GC cells by qRT-PCR, and western blot and assessed the relationship between TASP1 and GC cell proliferation and migration via CCK-8 and transwell assay. It was found that the expression of TASP1 in GC tissues or GC cell lines was significantly higher than that in normal adjacent tissues or normal cells. The proliferation and migration of GC cells were inhibited upon TASP1 knockdown. Mechanism investigation revealed that TASP1 promoted GC cell proliferation and migration through upregulating the p-AKT/AKT expression. TASP1 induced GC cell migration via the epithelial -mesenchymal transition (EMT) pathway. In conclusion, TASP1 promotes GC progression through the EMT and AKT/p-AKT pathway, and it may serve as a new potential biomarker and therapeutic target for GC.
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26
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Nagaratnam N, Delker SL, Jernigan R, Edwards TE, Snider J, Thifault D, Williams D, Nannenga BL, Stofega M, Sambucetti L, Hsieh JJ, Flint AJ, Fromme P, Martin-Garcia JM. Structural insights into the function of the catalytically active human Taspase1. Structure 2021; 29:873-885.e5. [PMID: 33784495 DOI: 10.1016/j.str.2021.03.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 02/07/2021] [Accepted: 03/10/2021] [Indexed: 12/15/2022]
Abstract
Taspase1 is an Ntn-hydrolase overexpressed in primary human cancers, coordinating cancer cell proliferation, invasion, and metastasis. Loss of Taspase1 activity disrupts proliferation of human cancer cells in vitro and in mouse models of glioblastoma. Taspase1 is synthesized as an inactive proenzyme, becoming active upon intramolecular cleavage. The activation process changes the conformation of a long fragment at the C-terminus of the α subunit, for which no full-length structural information exists and whose function is poorly understood. We present a cloning strategy to generate a circularly permuted form of Taspase1 to determine the crystallographic structure of active Taspase1. We discovered that this region forms a long helix and is indispensable for the catalytic activity of Taspase1. Our study highlights the importance of this element for the enzymatic activity of Ntn-hydrolases, suggesting that it could be a potential target for the design of inhibitors with potential to be developed into anticancer therapeutics.
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Affiliation(s)
- Nirupa Nagaratnam
- Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Silvia L Delker
- Beryllium Discovery Corp., with present address of UCB Biosciences, Bedford, MA 01730, USA
| | - Rebecca Jernigan
- Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Thomas E Edwards
- Beryllium Discovery Corp., with present address of UCB Biosciences, Bedford, MA 01730, USA
| | - Janey Snider
- Division of Biosciences, SRI International Menlo Park, Menlo Park, CA 94025, USA
| | - Darren Thifault
- Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Dewight Williams
- Eyring Materials Center, Arizona State University, Tempe, AZ 85257, USA
| | - Brent L Nannenga
- Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA; Chemical Engineering, School for Engineering of Matter, Transport, and Energy, Arizona State University, Tempe, AZ 85287, USA
| | - Mary Stofega
- Division of Biosciences, SRI International Menlo Park, Menlo Park, CA 94025, USA
| | - Lidia Sambucetti
- Division of Biosciences, SRI International Menlo Park, Menlo Park, CA 94025, USA
| | - James J Hsieh
- Molecular Oncology, Division of Oncology, Department of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Andrew J Flint
- Frederick National Lab for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
| | - Petra Fromme
- Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA.
| | - Jose M Martin-Garcia
- Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA; Department of Crystallography and Structural Biology, Institute of Physical-Chemistry "Rocasolano", Spanish National Research Council (CSIC), Madrid 28006, Spain.
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27
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Pasch P, Höing A, Ueclue S, Killa M, Voskuhl J, Knauer SK, Hartmann L. PEGylated sequence-controlled macromolecules using supramolecular binding to target the Taspase1/Importin α interaction. Chem Commun (Camb) 2021; 57:3091-3094. [PMID: 33625405 DOI: 10.1039/d0cc07139k] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
A novel strategy to inhibit the oncologically relevant protease Taspase1 is explored by developing PEGylated macromolecular ligands presenting the supramolecular binding motif guanidiniocarbonylpyrrole (GCP). Taspase1 requires interaction of its nuclear localization signal (NLS) with import receptor Importin α. We show the synthesis and effective interference of PEGylated multivalent macromolecular ligands with Taspase1-Importin α-complex formation.
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Affiliation(s)
- Peter Pasch
- Department for Organic Chemistry and Macromolecular Chemistry, Heinrich Heine University Düsseldorf, Universitätsstraße 1, Düsseldorf 40225, Germany.
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28
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Liu D, Fan W, Xu Y, Yu S, Liu W, Guo Z, Huang W, Zhou Z, Hou S. Genome-wide association studies demonstrate that TASP1 contributes to increased muscle fiber diameter. Heredity (Edinb) 2021; 126:991-999. [PMID: 33767369 DOI: 10.1038/s41437-021-00425-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 03/01/2021] [Accepted: 03/09/2021] [Indexed: 12/13/2022] Open
Abstract
Muscle fiber diameter is an economically important trait because it affects meat yield and quality. However, the genetic basis underlying muscle fiber diameter has not been determined. In this study, we collected THREE muscular histological phenotypes in 479 ducks from an F2 segregating population generated by mallard × Pekin duck crosses. We performed genome-wide association studies (GWAS) and identified a quantitative trait locus (QTL) significantly associated with muscle fiber diameter on chromosome 3. Then, we discovered the selection signatures using the fixation index among 40 mallards and 30 Pekin ducks in this QTL region. Furthermore, we characterized the recombination event in this QTL region and identified a 6-kb block located on TASP1 that was significantly associated with muscle fiber diameter. Finally, five SNPs were screened as potential causative mutations within the 6-kb block. In conclusion, we demonstrated that TASP1 contributes to an increase in muscle fiber diameter, which helps to characterize muscle development and contributes to the genetic improvement of meat yield and quality in livestock.
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Affiliation(s)
- Dapeng Liu
- Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs; State Key Laboratory of Animal Nutrition; Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, PR China
| | - Wenlei Fan
- College of Food Science and Engineering, Qingdao Agricultural University, Qingdao, PR China
| | - Yaxi Xu
- Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs; State Key Laboratory of Animal Nutrition; Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, PR China
| | - Simeng Yu
- Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs; State Key Laboratory of Animal Nutrition; Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, PR China
| | - Wenjing Liu
- Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs; State Key Laboratory of Animal Nutrition; Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, PR China.,College of Animal Science, Qingdao Agricultural University, Qingdao, PR China
| | - Zhanbao Guo
- Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs; State Key Laboratory of Animal Nutrition; Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, PR China
| | - Wei Huang
- Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs; State Key Laboratory of Animal Nutrition; Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, PR China
| | - Zhengkui Zhou
- Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs; State Key Laboratory of Animal Nutrition; Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, PR China.
| | - Shuisheng Hou
- Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs; State Key Laboratory of Animal Nutrition; Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, PR China.
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29
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Jiang J, Liu B, Liu R, Yang W. Overexpression of Taspase 1 Predicts Poor Prognosis in Patients with Hepatocellular Carcinoma. Cancer Manag Res 2021; 13:2517-2537. [PMID: 33758547 PMCID: PMC7981154 DOI: 10.2147/cmar.s296069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 02/25/2021] [Indexed: 12/16/2022] Open
Abstract
Background Taspase 1 (TASP1) is a highly conserved protease involved in site-specific proteolysis. Existing researches have revealed a link between TASP1 expression and carcinogenesis. However, limited data are available regarding the prognosis and functions of TASP1 in hepatocellular carcinoma (HCC). Methods Western Blotting and qRT-PCR were employed to evaluate the level of TASP1 in HCC cell lines and clinical specimens. TASP1 expression was further calculated in clinical specimens by immunohistochemistry and the mRNA level of TASP1 in HCC was analyzed using Oncomine and UALCAN databases. The TASP1 promoter methylation modification was shown via MEXPRESS and UALCAN. The association between TASP1 expression and postoperative prognosis was evaluated using Kaplan–Meier and Cox regression analysis in clinical patients. The effect of TASP1 on HCC prognosis was analyzed via Kaplan-Meier plotter, GEPIA and UALCAN. Additionally, the regulators, kinases, miRNA and transcription factor targets of TASP1 were identified using LinkedOmics. Moreover, cBioPortal was used to detect the genetic alteration of TASP1. Finally, TIMER was utilized to assess the relation between TASP1 and the immune cell infiltration, whereas the correlation of TASP1 with three immune factors was detected through TISIDB. Results TASP1 expression was increased in HCC cell lines and HCC tissues. CNV and DNA methylation of TASP1 were changed. Survival analysis revealed that high TASP1 expression was correlated with overall survival (OS). Functional network analysis about TASP1 in HCC showed that the double-strand break repair, peptidyl-threonine modification, spindle organization, peptidyl-lysine modification and microtubule-based movement were modulated. Furthermore, TASP1 expression revealed puissant relation to the infiltration of immune cells and three immune factors in HCC. Conclusion These data indicate that TASP1 may act as a potential prognostic marker in HCC and regulate HCC via multiple mechanisms.
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Affiliation(s)
- Jie Jiang
- Department of Gastroenterology and Hepatology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Bin Liu
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
| | - Ruilin Liu
- Department of Pulmonary, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Wenzhuo Yang
- Department of Gastroenterology and Hepatology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
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Grigsby SM, Friedman A, Chase J, Waas B, Ropa J, Serio J, Shen C, Muntean AG, Maillard I, Nikolovska-Coleska Z. Elucidating the Importance of DOT1L Recruitment in MLL-AF9 Leukemia and Hematopoiesis. Cancers (Basel) 2021; 13:642. [PMID: 33562706 PMCID: PMC7914713 DOI: 10.3390/cancers13040642] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/27/2021] [Accepted: 01/31/2021] [Indexed: 12/14/2022] Open
Abstract
MLL1 (KMT2a) gene rearrangements underlie the pathogenesis of aggressive MLL-driven acute leukemia. AF9, one of the most common MLL-fusion partners, recruits the histone H3K79 methyltransferase DOT1L to MLL target genes, constitutively activating transcription of pro-leukemic targets. DOT1L has emerged as a therapeutic target in patients with MLL-driven leukemia. However, global DOT1L enzymatic inhibition may lead to off-target toxicities in non-leukemic cells that could decrease the therapeutic index of DOT1L inhibitors. To bypass this problem, we developed a novel approach targeting specific protein-protein interactions (PPIs) that mediate DOT1L recruitment to MLL target genes, and compared the effects of enzymatic and PPIs inhibition on leukemic and non-leukemic hematopoiesis. MLL-AF9 cell lines were engineered to carry mutant DOT1L constructs with a defective AF9 interaction site or lacking enzymatic activity. In cell lines expressing a DOT1L mutant with defective AF9 binding, we observed complete disruption of DOT1L recruitment to critical target genes and inhibition of leukemic cell growth. To evaluate the overall impact of DOT1L loss in non-leukemic hematopoiesis, we first assessed the impact of acute Dot1l inactivation in adult mouse bone marrow. We observed a rapid reduction in myeloid progenitor cell numbers within 7 days, followed by a loss of long-term hematopoietic stem cells. Furthermore, WT and PPI-deficient DOT1L mutants but not an enzymatically inactive DOT1L mutant were able to rescue sustained hematopoiesis. These data show that the AF9-DOT1L interaction is dispensable in non-leukemic hematopoiesis. Our findings support targeting of the MLL-AF9-DOT1L interaction as a promising therapeutic strategy that is selectively toxic to MLL-driven leukemic cells.
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Affiliation(s)
- Sierrah M. Grigsby
- Molecular and Celular Graduate Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48104, USA; (S.M.G.); (J.R.); (J.S.); (C.S.); (A.G.M.)
| | - Ann Friedman
- Department of Internal Medicine, Life Sciences Institute, University of Michigan Medical School, Ann Arbor, MI 48104, USA; (A.F.); (J.C.); (B.W.); (I.M.)
| | - Jennifer Chase
- Department of Internal Medicine, Life Sciences Institute, University of Michigan Medical School, Ann Arbor, MI 48104, USA; (A.F.); (J.C.); (B.W.); (I.M.)
| | - Bridget Waas
- Department of Internal Medicine, Life Sciences Institute, University of Michigan Medical School, Ann Arbor, MI 48104, USA; (A.F.); (J.C.); (B.W.); (I.M.)
| | - James Ropa
- Molecular and Celular Graduate Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48104, USA; (S.M.G.); (J.R.); (J.S.); (C.S.); (A.G.M.)
| | - Justin Serio
- Molecular and Celular Graduate Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48104, USA; (S.M.G.); (J.R.); (J.S.); (C.S.); (A.G.M.)
| | - Chenxi Shen
- Molecular and Celular Graduate Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48104, USA; (S.M.G.); (J.R.); (J.S.); (C.S.); (A.G.M.)
| | - Andrew G. Muntean
- Molecular and Celular Graduate Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48104, USA; (S.M.G.); (J.R.); (J.S.); (C.S.); (A.G.M.)
- Rogel Cancer Center, Michigan Medicine, University of Michigan Medical School, Ann Arbor, MI 48104, USA
| | - Ivan Maillard
- Department of Internal Medicine, Life Sciences Institute, University of Michigan Medical School, Ann Arbor, MI 48104, USA; (A.F.); (J.C.); (B.W.); (I.M.)
| | - Zaneta Nikolovska-Coleska
- Molecular and Celular Graduate Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48104, USA; (S.M.G.); (J.R.); (J.S.); (C.S.); (A.G.M.)
- Rogel Cancer Center, Michigan Medicine, University of Michigan Medical School, Ann Arbor, MI 48104, USA
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Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia. Nat Genet 2021; 53:1586-1596. [PMID: 34663924 PMCID: PMC8571097 DOI: 10.1038/s41588-021-00941-9] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 08/12/2021] [Indexed: 11/10/2022]
Abstract
Acute myeloid and lymphoid leukemias often harbor chromosomal translocations involving the KMT2A gene, encoding the KMT2A lysine methyltransferase (also known as mixed-lineage leukemia-1), and produce in-frame fusions of KMT2A to other chromatin-regulatory proteins. Here we map fusion-specific targets across the genome for diverse KMT2A oncofusion proteins in cell lines and patient samples. By modifying CUT&Tag chromatin profiling for full automation, we identify common and tumor-subtype-specific sites of aberrant chromatin regulation induced by KMT2A oncofusion proteins. A subset of KMT2A oncofusion-binding sites are marked by bivalent (H3K4me3 and H3K27me3) chromatin signatures, and single-cell CUT&Tag profiling reveals that these sites display cell-to-cell heterogeneity suggestive of lineage plasticity. In addition, we find that aberrant enrichment of H3K4me3 in gene bodies is sensitive to Menin inhibitors, demonstrating the utility of automated chromatin profiling for identifying therapeutic vulnerabilities. Thus, integration of automated and single-cell CUT&Tag can uncover epigenomic heterogeneity within patient samples and predict sensitivity to therapeutic agents.
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Aberrant Activity of Histone-Lysine N-Methyltransferase 2 (KMT2) Complexes in Oncogenesis. Int J Mol Sci 2020; 21:ijms21249340. [PMID: 33302406 PMCID: PMC7762615 DOI: 10.3390/ijms21249340] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/04/2020] [Accepted: 12/06/2020] [Indexed: 02/06/2023] Open
Abstract
KMT2 (histone-lysine N-methyltransferase subclass 2) complexes methylate lysine 4 on the histone H3 tail at gene promoters and gene enhancers and, thus, control the process of gene transcription. These complexes not only play an essential role in normal development but have also been described as involved in the aberrant growth of tissues. KMT2 mutations resulting from the rearrangements of the KMT2A (MLL1) gene at 11q23 are associated with pediatric mixed-lineage leukemias, and recent studies demonstrate that KMT2 genes are frequently mutated in many types of human cancers. Moreover, other components of the KMT2 complexes have been reported to contribute to oncogenesis. This review summarizes the recent advances in our knowledge of the role of KMT2 complexes in cell transformation. In addition, it discusses the therapeutic targeting of different components of the KMT2 complexes.
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van den Boom J, Hensel A, Trusch F, Matena A, Siemer S, Guel D, Docter D, Höing A, Bayer P, Stauber RH, Knauer SK. The other side of the corona: nanoparticles inhibit the protease taspase1 in a size-dependent manner. NANOSCALE 2020; 12:19093-19103. [PMID: 32662484 DOI: 10.1039/d0nr01631d] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
When nanoparticles enter a physiological environment, they rapidly adsorb biomolecules, in particular cellular proteins. This biological coating, the so-called nanoparticle protein corona, undoubtedly affects the biological identity and potential cytotoxicity of the nanomaterial. To elucidate a possible impact on the adsorbed biomolecules, we focused on an important group of players in cellular homeostasis, namely proteolytic enzymes. We could demonstrate that amorphous silica nanoparticles are not only able to bind to the oncologically relevant threonine protease Taspase1 as revealed by microscale thermophoresis and fluorescence anisotropy measurements, but moreover inhibit its proteolytic activity in a non-competitive manner. As revealed by temperature-dependent unfolding and CD spectroscopy, binding did not alter the stability of Taspase1 or its secondary structure. Noteworthy, inhibition of protein function seems not a general feature of nanoparticles, as several control enzymes were not affected in their proteolytic activity. Our data suggests that nanoparticles bind Taspase1 as an αβ-dimer in a single layer without conformational change, resulting in noncompetitive inhibition that is either allostery-like or occludes the active site. Nanoparticle-based inhibition of Taspase1 could be also achieved in cell lysates and in live cells as shown by the use of a protease-specific cellular cleavage biosensor. Collectively, we could demonstrate that nanoparticles could not only bind but also selectively inhibit cellular enzymes, which might explain observed cytotoxicity but might serve as a starting point for the development of nanoparticle-based inhibitors as therapeutics.
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Affiliation(s)
- Johannes van den Boom
- Structural and Medicinal Biochemistry, Department of Biology, University Duisburg-Essen and Zentrum für Molekulare Biotechnologie (ZMB), Universitätsstrasse 5, Essen, 45141 Germany.
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Bian J, Dannappel M, Wan C, Firestein R. Transcriptional Regulation of Wnt/β-Catenin Pathway in Colorectal Cancer. Cells 2020; 9:cells9092125. [PMID: 32961708 PMCID: PMC7564852 DOI: 10.3390/cells9092125] [Citation(s) in RCA: 159] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/14/2020] [Accepted: 09/17/2020] [Indexed: 02/07/2023] Open
Abstract
The Wnt/β-catenin signaling pathway exerts integral roles in embryogenesis and adult homeostasis. Aberrant activation of the pathway is implicated in growth-associated diseases and cancers, especially as a key driver in the initiation and progression of colorectal cancer (CRC). Loss or inactivation of Adenomatous polyposis coli (APC) results in constitutive activation of Wnt/β-catenin signaling, which is considered as an initiating event in the development of CRC. Increased Wnt/β-catenin signaling is observed in virtually all CRC patients, underscoring the importance of this pathway for therapeutic intervention. Prior studies have deciphered the regulatory networks required for the cytoplasmic stabilisation or degradation of the Wnt pathway effector, β-catenin. However, the mechanism whereby nuclear β-catenin drives or inhibits expression of Wnt target genes is more diverse and less well characterised. Here, we describe a brief synopsis of the core canonical Wnt pathway components, set the spotlight on nuclear mediators and highlight the emerging role of chromatin regulators as modulators of β-catenin-dependent transcription activity and oncogenic output.
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Affiliation(s)
- Jia Bian
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; (J.B.); (M.D.); (C.W.)
- Department of Molecular and Translational Science, Monash University, Clayton, VIC 3800, Australia
| | - Marius Dannappel
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; (J.B.); (M.D.); (C.W.)
- Department of Molecular and Translational Science, Monash University, Clayton, VIC 3800, Australia
| | - Chunhua Wan
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; (J.B.); (M.D.); (C.W.)
- Department of Molecular and Translational Science, Monash University, Clayton, VIC 3800, Australia
| | - Ron Firestein
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia; (J.B.); (M.D.); (C.W.)
- Department of Molecular and Translational Science, Monash University, Clayton, VIC 3800, Australia
- Correspondence:
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Antunes ETB, Ottersbach K. The MLL/SET family and haematopoiesis. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2020; 1863:194579. [PMID: 32389825 PMCID: PMC7294230 DOI: 10.1016/j.bbagrm.2020.194579] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 04/08/2020] [Accepted: 04/30/2020] [Indexed: 12/11/2022]
Abstract
As demonstrated through early work in Drosophila, members of the MLL/SET family play essential roles during embryonic development through their participation in large protein complexes that are central to epigenetic regulation of gene expression. One of its members, MLL1, has additionally received a lot of attention as it is a potent oncogenic driver in different types of leukaemia when aberrantly fused to a large variety of partners as a result of chromosomal translocations. Its exclusive association with cancers of the haematopoietic system has prompted a large number of investigations into the role of MLL/SET proteins in haematopoiesis, a summary of which was attempted in this review. Interestingly, MLL-rearranged leukaemias are particularly prominent in infant and paediatric leukaemia, which commonly initiate in utero. This, together with the known function of MLL/SET proteins in embryonic development, has focussed research efforts in recent years on understanding the role of this protein family in developmental haematopoiesis and how this may be subverted by MLL oncofusions in infant leukaemia. A detailed understanding of these prenatal events is essential for the development of new treatments that improve the survival specifically of this very young patient group.
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Affiliation(s)
- Eric T B Antunes
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Scotland, UK
| | - Katrin Ottersbach
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Scotland, UK.
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The efficiency of murine MLL-ENL-driven leukemia initiation changes with age and peaks during neonatal development. Blood Adv 2020; 3:2388-2399. [PMID: 31405949 DOI: 10.1182/bloodadvances.2019000554] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 07/16/2019] [Indexed: 12/22/2022] Open
Abstract
MLL rearrangements are translocation mutations that cause both acute lymphoblastic leukemia and acute myeloid leukemia (AML). These translocations can occur as sole clonal driver mutations in infant leukemias, suggesting that fetal or neonatal hematopoietic progenitors may be exquisitely sensitive to transformation by MLL fusion proteins. To test this possibility, we used transgenic mice to induce one translocation product, MLL-ENL, during fetal, neonatal, juvenile and adult stages of life. When MLL-ENL was induced in fetal or neonatal mice, almost all died of AML. In contrast, when MLL-ENL was induced in adult mice, most survived for >1 year despite sustained transgene expression. AML initiation was most efficient when MLL-ENL was induced in neonates, and even transient suppression of MLL-ENL in neonates could prevent AML in most mice. MLL-ENL target genes were induced more efficiently in neonatal progenitors than in adult progenitors, consistent with the distinct AML initiation efficiencies. Interestingly, transplantation stress mitigated the developmental barrier to leukemogenesis. Since fetal/neonatal progenitors were highly competent to initiate MLL-ENL-driven AML, we tested whether Lin28b, a fetal master regulator, could accelerate leukemogenesis. Surprisingly, Lin28b suppressed AML initiation rather than accelerating it. This may explain why MLL rearrangements often occur before birth in human infant leukemia patients, but transformation usually does not occur until after birth, when Lin28b levels decline. Our findings show that the efficiency of MLL-ENL-driven AML initiation changes through the course of pre- and postnatal development, and developmental programs can be manipulated to impede transformation.
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37
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Ge M, Li D, Qiao Z, Sun Y, Kang T, Zhu S, Wang S, Xiao H, Zhao C, Shen S, Xu Z, Liu H. Restoring MLL reactivates latent tumor suppression-mediated vulnerability to proteasome inhibitors. Oncogene 2020; 39:5888-5901. [PMID: 32733069 PMCID: PMC7471105 DOI: 10.1038/s41388-020-01408-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/16/2020] [Accepted: 07/23/2020] [Indexed: 12/15/2022]
Abstract
MLL undergoes multiple distinct chromosomal translocations to yield aggressive leukemia with dismal outcomes. Besides their well-established role in leukemogenesis, MLL fusions also possess latent tumor-suppressive activity, which can be exploited as effective cancer treatment strategies using pharmacological means such as proteasome inhibitors (PIs). Here, using MLL-rearranged xenografts and MLL leukemic cells as models, we show that wild-type MLL is indispensable for the latent tumor-suppressive activity of MLL fusions. MLL dysfunction, shown as loss of the chromatin accumulation and subsequent degradation of MLL, compromises the latent tumor suppression of MLL-AF4 and is instrumental for the acquired PI resistance. Mechanistically, MLL dysfunction is caused by chronic PI treatment-induced epigenetic reprogramming through the H2Bub-ASH2L-MLL axis and can be specifically restored by histone deacetylase (HDAC) inhibitors, which induce histone acetylation and recruits MLL on chromatin to promote cell cycle gene expression. Our findings not only demonstrate the mechanism underlying the inevitable acquisition of PI resistance in MLL leukemic cells, but also illustrate that preventing the emergence of PI-resistant cells constitutes a novel rationale for combination therapy with PIs and HDAC inhibitors in MLL leukemias.
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Affiliation(s)
- Maolin Ge
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Dan Li
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Zhi Qiao
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China
| | - Yan Sun
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Ting Kang
- Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, 200092, Shanghai, China
| | - Shouhai Zhu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Shifen Wang
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 350001, Fuzhou, China
| | - Hua Xiao
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China
| | - Chunjun Zhao
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China
| | - Shuhong Shen
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology & Oncology, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
| | - Zhenshu Xu
- Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, 350001, Fuzhou, China.
| | - Han Liu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
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Wang F, Li P, Shao Y, Li Y, Zhang K, Li M, Wang R, Zheng S, Wang Y, Song S, Feng S, Liu F, Xiao W, Li X. Site-specific proteolytic cleavage prevents ubiquitination and degradation of human REV3L, the catalytic subunit of DNA polymerase ζ. Nucleic Acids Res 2020; 48:3619-3637. [PMID: 32064513 PMCID: PMC7144948 DOI: 10.1093/nar/gkaa096] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 02/02/2020] [Accepted: 02/04/2020] [Indexed: 01/18/2023] Open
Abstract
REV3L, the catalytic subunit of DNA polymerase ζ (Pol ζ), is indispensable for translesion DNA synthesis, which protects cells from deleterious DNA lesions resulting from various intrinsic and environmental sources. However, REV3L lacks a proofreading exonuclease activity and consequently bypasses DNA lesions at the expense of increased mutations, which poses a severe threat to genome stability. Here we report a site-specific proteolytic event of human REV3L. We show that REV3L is cleaved by a threonine aspartase, Taspase1 (TASP1), to generate an N-terminal 70-kDa fragment (N70) and a polypeptide carrying the C-terminal polymerase catalytic domain in human cells. Strikingly, such a post-translational cleavage event plays a vital role in controlling REV3L stability by preventing ubiquitination and proteasome-mediated degradation of REV3L. Indicative of the biological importance of the above REV3L post-translational processing, cellular responses to UV and cisplatin-induced DNA lesions are markedly impaired in human HCT116 cell derivatives bearing defined point mutations in the endogenous REV3L gene that compromise REV3L cleavage. These findings establish a new paradigm in modulating the abundance of REV3L through site-specific proteolysis in human cells.
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Affiliation(s)
- Fengting Wang
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
| | - Pan Li
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
| | - Yuan Shao
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
| | - Yanyan Li
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
| | - Kai Zhang
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
| | - Miaomiao Li
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
| | - Rong Wang
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
| | - Shuo Zheng
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
| | - Yingying Wang
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
| | - Sen Song
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
| | - Shiguo Feng
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
| | - Fei Liu
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
| | - Wei Xiao
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
| | - Xialu Li
- Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China
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Park K, Kim JA, Kim J. Transcriptional regulation by the KMT2 histone H3K4 methyltransferases. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2020; 1863:194545. [DOI: 10.1016/j.bbagrm.2020.194545] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 01/21/2020] [Accepted: 03/13/2020] [Indexed: 01/09/2023]
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40
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Fontana P, Passaretti FF, Maioli M, Cantalupo G, Scarano F, Lonardo F. Clinical and molecular spectrum of Wiedemann-Steiner syndrome, an emerging member of the chromatinopathy family. World J Med Genet 2020; 9:1-11. [DOI: 10.5496/wjmg.v9.i1.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 04/19/2020] [Accepted: 05/14/2020] [Indexed: 02/06/2023] Open
Abstract
Wiedemann-Steiner syndrome (OMIM #605130) is a rare congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature; consistent facial features, including long eyelashes, thick or arched eyebrows with a lateral flare, wide nasal bridge, and downslanting and vertically narrow palpebral fissures; mild to moderate intellectual disability; behavioral difficulties; and hypertrichosis on the back. It is caused by heterozygous pathogenic variants in KMT2A. This gene has an established role in histone methylation, which explains the overlap of Wiedemann-Steiner syndrome with other chromatinopathies, a heterogeneous group of syndromic conditions that share a common trigger: The disruption of one of the genes involved in chromatin modification, leading to dysfunction of the epigenetic machinery.
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Affiliation(s)
- Paolo Fontana
- Medical Genetics Unit, San Pio Hospital, Benevento 82100, Italy
| | | | - Marianna Maioli
- Medical Genetics Unit, San Pio Hospital, Benevento 82100, Italy
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Banday S, Farooq Z, Ganai SA, Altaf M. Therapeutic strategies against hDOT1L as a potential drug target in MLL-rearranged leukemias. Clin Epigenetics 2020; 12:73. [PMID: 32450905 PMCID: PMC7249331 DOI: 10.1186/s13148-020-00860-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 05/12/2020] [Indexed: 11/17/2022] Open
Abstract
Therapeutic intervention of proteins participating in chromatin-mediated signaling with small-molecules is a novel option to reprogram expression networks for restraining disease states. Protein methyltransferases form the prominent family of such proteins regulating gene expression via epigenetic mechanisms thereby representing novel targets for pharmacological intervention. Disruptor of telomeric silencing, hDot1L is the only non-SET domain containing histone methyltransferase that methylates histone H3 at lysine 79. H3K79 methylation mediated by hDot1L plays a crucial role in mixed lineage leukemia (MLL) pathosis. MLL fusion protein mediated mistargeting of DOT1L to aberrant gene locations results in ectopic H3K79 methylation culminating in aberrant expression of leukemogenic genes like HOXA9 and MEIS1. hDOT1L has thus been proposed as a potential target for therapeutic intervention in MLL. This review presents the general overview of hDOT1L and its functional role in distinct biological processes. Furthermore, we discuss various therapeutic strategies against hDOT1L as a promising drug target to vanquish therapeutically challenging MLL.
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Affiliation(s)
- Shahid Banday
- Chromatin and Epigenetics Lab, Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, 190006, India
| | - Zeenat Farooq
- Chromatin and Epigenetics Lab, Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, 190006, India
| | - Shabir Ahmad Ganai
- Chromatin and Epigenetics Lab, Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, 190006, India.,Present Address: Division of Basic Sciences and Humanities, Faculty of Agriculture, SKUAST-Kashmir, Wadura, Sopore, Jammu and Kashmir, 193201, India
| | - Mohammad Altaf
- Chromatin and Epigenetics Lab, Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, 190006, India. .,Centre for Interdisciplinary Research and Innovations, University of Kashmir, Hazratbal, Srinagar, 190006, India.
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42
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Basu S, Nandy A, Biswas D. Keeping RNA polymerase II on the run: Functions of MLL fusion partners in transcriptional regulation. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2020; 1863:194563. [PMID: 32348849 DOI: 10.1016/j.bbagrm.2020.194563] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 01/13/2020] [Accepted: 04/13/2020] [Indexed: 12/21/2022]
Abstract
Since the identification of key MLL fusion partners as transcription elongation factors regulating expression of HOX cluster genes during hematopoiesis, extensive work from the last decade has resulted in significant progress in our overall mechanistic understanding of role of MLL fusion partner proteins in transcriptional regulation of diverse set of genes beyond just the HOX cluster. In this review, we are going to detail overall understanding of role of MLL fusion partner proteins in transcriptional regulation and thus provide mechanistic insights into possible MLL fusion protein-mediated transcriptional misregulation leading to aberrant hematopoiesis and leukemogenesis.
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Affiliation(s)
- Subham Basu
- Laboratory of Transcription Biology, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata 32, India
| | - Arijit Nandy
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Debabrata Biswas
- Laboratory of Transcription Biology, Molecular Genetics Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata 32, India.
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43
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Takahashi S, Yokoyama A. The molecular functions of common and atypical MLL fusion protein complexes. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2020; 1863:194548. [PMID: 32320750 DOI: 10.1016/j.bbagrm.2020.194548] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 02/19/2020] [Accepted: 03/31/2020] [Indexed: 12/17/2022]
Abstract
Mixed-lineage leukemia (MLL) fuses with a variety of partners to produce a functionally altered MLL complex that is not expressed in normal cells, which transforms normal hematopoietic progenitors into leukemia cells. Because more than 80 fusion partners have been identified to date, the molecular functions of MLL fusion protein complexes appear diverse. However, over the past decade, the common functions utilized for leukemic transformation have begun to be elucidated. It appears that most (if not all) MLL fusion protein complexes utilize the AF4/ENL/P-TEFb and DOT1L complexes to some extent. Based on an understanding of the underlying molecular mechanisms, several molecular targeting drugs are being developed, opening paths to novel therapies. Here, we review the recent progress made in identifying the molecular functions of various MLL fusions and categorize the numerous fusion partners into several functionally-distinct groups to help discern commonalities and differences among various MLL fusion protein complexes.
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Affiliation(s)
- Satoshi Takahashi
- Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan; Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Akihiko Yokoyama
- Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Japan; National Cancer Center Research Institute, Tokyo, Japan.
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Zhang Y, Du P, Li Y, Zhu Q, Song X, Liu S, Hao J, Liu L, Liu F, Hu Y, Jiang L, Ma Q, Lu W, Liu Y. TASP1 Promotes Gallbladder Cancer Cell Proliferation and Metastasis by Up-regulating FAM49B via PI3K/AKT Pathway. Int J Biol Sci 2020; 16:739-751. [PMID: 32071545 PMCID: PMC7019140 DOI: 10.7150/ijbs.40516] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 12/06/2019] [Indexed: 12/19/2022] Open
Abstract
The highly conserved protease TASP1 not only takes part in critical site-specific proteolysis, but also plays an important role in numerous liquid and solid malignancies. However, the TASP1 expression and its biological regulation function in malignant gallbladder carcinoma (GBC) remain fully unknown. Here we observed that TASP1 levels were substantially overexpressed in GBC samples compared with non-tumor tissues. High TASP1 level was closely associated with T stage and metastasis, and was also correlated with poor prognosis in GBC patients. The depletion of TASP1 inhibited GBC cell proliferation and metastasis in vitro and in vivo. Furthermore, we first revealed that FAM49B had biological function and was positively regulated by TASP1 activating PI3K/AKT signaling pathway in GBC. At the same time, FAM49B also promoted GBC cell proliferation and migration. Inhibition of PI3K/AKT with LY294002 or FAM49B expression abrogated Myc-TASP1/Lv-shTASP1-induced GBC cell proliferation and motility. In conclusion, these findings demonstrate that TASP1 is critical for GBC progression via TASP1-PI3K/AKT-FAM49B axis and it may be a novel prognostic factor. The therapeutic targeting TASP1 may be a potential treatment approach for GBC patients.
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Affiliation(s)
- Yijian Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Pengcheng Du
- Department of General Surgery, Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang 330006, China
| | - Yang Li
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Qin Zhu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Xiaoling Song
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Shibo Liu
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Jiaqi Hao
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Liguo Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Fatao Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Yunping Hu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Lin Jiang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Qiang Ma
- Department of Thyroid Oncology, Shanghai East Hospital Affiliated to Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China
| | - Wei Lu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
| | - Yingbin Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, 1665 Kongjiang Road, Shanghai 200092, China
- Shanghai Research Center of Biliary Tract Disease, 1665 Kongjiang Road, Shanghai 200092, China
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Beard HA, Barniol-Xicota M, Yang J, Verhelst SHL. Discovery of Cellular Roles of Intramembrane Proteases. ACS Chem Biol 2019; 14:2372-2388. [PMID: 31287658 DOI: 10.1021/acschembio.9b00404] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Intramembrane proteases (IMPs) are localized within lipid bilayers of membranes-either the cell membrane or membranes of various organelles. Cleavage of substrates often results in release from the membrane, leading to a downstream biological effect. This mechanism allows different signaling events to happen through intramembrane proteolysis. Over the years, various mechanistically distinct families of IMPs have been discovered, but the research progress has generally been slower than for soluble proteases due to the challenges associated with membrane proteins. In this review we summarize how each mechanistic family of IMPs was discovered, which chemical tools are available for the study of IMPs, and which techniques have been developed for the discovery of IMP substrates. Finally, we discuss the various roles in cellular physiology of some of these IMPs.
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Affiliation(s)
- Hester A. Beard
- KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Chemical Biology, Herestr. 49, 3000 Leuven, Belgium
| | - Marta Barniol-Xicota
- KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Chemical Biology, Herestr. 49, 3000 Leuven, Belgium
| | - Jian Yang
- KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Chemical Biology, Herestr. 49, 3000 Leuven, Belgium
| | - Steven H. L. Verhelst
- KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Chemical Biology, Herestr. 49, 3000 Leuven, Belgium
- Leibniz Institute for Analytical Sciences ISAS, Otto-Hahn-Str. 6b, 44227 Dortmund, Germany
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Zhu S, Chen Z, Wang R, Tan Y, Ge M, Sun Y, Li D, Hu Y, Zhao C, Chen Z, Chen S, Liu H. MLL is required for miRNA-mediated translational repression. Cell Discov 2019; 5:43. [PMID: 31636956 PMCID: PMC6796902 DOI: 10.1038/s41421-019-0111-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 07/05/2019] [Indexed: 01/08/2023] Open
Affiliation(s)
- Shouhai Zhu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Zhihong Chen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Ruiheng Wang
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Yuting Tan
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Maolin Ge
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Yan Sun
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Dan Li
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Yutian Hu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Chunjun Zhao
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Zhu Chen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Saijuan Chen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Han Liu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
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Crump NT, Milne TA. Why are so many MLL lysine methyltransferases required for normal mammalian development? Cell Mol Life Sci 2019; 76:2885-2898. [PMID: 31098676 PMCID: PMC6647185 DOI: 10.1007/s00018-019-03143-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 05/10/2019] [Indexed: 12/12/2022]
Abstract
The mixed lineage leukemia (MLL) family of proteins became known initially for the leukemia link of its founding member. Over the decades, the MLL family has been recognized as an important class of histone H3 lysine 4 (H3K4) methyltransferases that control key aspects of normal cell physiology and development. Here, we provide a brief history of the discovery and study of this family of proteins. We address two main questions: why are there so many H3K4 methyltransferases in mammals; and is H3K4 methylation their key function?
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Affiliation(s)
- Nicholas T Crump
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Thomas A Milne
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
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48
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Transcriptional addiction in mixed lineage leukemia: new avenues for target therapies. BLOOD SCIENCE 2019; 1:50-56. [PMID: 35402805 PMCID: PMC8975088 DOI: 10.1097/bs9.0000000000000011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 07/02/2019] [Indexed: 11/25/2022] Open
Abstract
Mixed lineage leukemia (MLL) is an aggressive and refractory blood cancer that predominantly occurs in pediatric patients and is often associated with poor prognosis and dismal outcomes. Thus far, no effective target therapy for the treatment of MLL leukemia is available. MLL leukemia is caused by the rearrangement of MLL genes at 11q23, which generates various MLL chimeric proteins that promote leukemogenesis through transcriptional misregulation of MLL target genes. Biochemical studies on MLL chimeras have identified that the most common partners exist in the superelongation complex (SEC) and DOT1L complex, which activate or sustain MLL target gene expression through processive transcription elongation. The results of these studies indicate a transcription-related mechanism for MLL leukemogenesis and maintenance. In this study, we first review the history of MLL leukemia and its related clinical features. Then, we discuss the biological functions of MLL and MLL chimeras, significant cooperating events, and transcriptional addiction mechanisms in MLL leukemia with an emphasis on potential and rational therapy development. Collectively, we believe that targeting the transcriptional addiction mediated by SEC and the DOT1L complex will provide new avenues for target therapies in MLL leukemia and serve as a novel paradigm for targeting transcriptional addiction in other cancers.
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49
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Balkin DM, Poranki M, Forester CM, Dorsey MJ, Slavotinek A, Pomerantz JH. TASP1 mutation in a female with craniofacial anomalies, anterior segment dysgenesis, congenital immunodeficiency and macrocytic anemia. Mol Genet Genomic Med 2019; 7:e818. [PMID: 31350873 PMCID: PMC6732342 DOI: 10.1002/mgg3.818] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 05/16/2019] [Indexed: 12/29/2022] Open
Abstract
Background Threonine Aspartase 1 (Taspase 1) is a highly conserved site‐specific protease whose substrates are broad‐acting nuclear transcription factors that govern diverse biological programs, such as organogenesis, oncogenesis, and tumor progression. To date, no single base pair mutations in Taspase 1 have been implicated in human disease. Methods A female infant with a new pattern of diagnostic abnormalities was identified, including severe craniofacial anomalies, anterior and posterior segment dysgenesis, immunodeficiency, and macrocytic anemia. Trio‐based whole exome sequencing was performed to identify disease‐causing variants. Results Whole exome sequencing revealed a normal female karyotype (46,XX) without increased regions of homozygosity. The proband was heterozygous for a de novo missense variant, c.1027G>A predicting p.(Val343Met), in the TASP1 gene (NM_017714.2). This variant has not been observed in population databases and is predicted to be deleterious. Conclusion One human patient has been reported previously with a large TASP1 deletion and substantial evidence exists regarding the role of several known Taspase 1 substrates in human craniofacial and hematopoietic disorders. Moreover, Taspase 1 deficiency in mice results in craniofacial, ophthalmological and structural brain defects. Taken together, there exists substantial evidence to conclude that the TASP1 variant, p.(Val343Met), is pathogenic in this patient.
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Affiliation(s)
- Daniel M Balkin
- Division of Plastic and Reconstructive Surgery, Department of Surgery, University of California San Francisco, San Francisco, California.,Craniofacial Center, University of California San Francisco, San Francisco, California
| | - Menitha Poranki
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California
| | - Craig M Forester
- Division of Pediatric Allergy, Immunology & Bone Marrow Transplantation, Department of Pediatrics, University of California San Francisco, San Francisco, California
| | - Morna J Dorsey
- Division of Pediatric Allergy, Immunology & Bone Marrow Transplantation, Department of Pediatrics, University of California San Francisco, San Francisco, California
| | - Anne Slavotinek
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California
| | - Jason H Pomerantz
- Division of Plastic and Reconstructive Surgery, Department of Surgery, University of California San Francisco, San Francisco, California.,Craniofacial Center, University of California San Francisco, San Francisco, California.,Department of Orofacial Sciences, University of California San Francisco, San Francisco, California
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50
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Suleiman J, Riedhammer KM, Jicinsky T, Mundt M, Werner L, Gusic M, Burgemeister AL, Alsaif HS, Abdulrahim M, Moghrabi NN, Nicolas-Jilwan M, AlSayed M, Bi W, Sampath S, Alkuraya FS, El-Hattab AW. Homozygous loss-of-function variants of TASP1, a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies. Hum Mutat 2019; 40:1985-1992. [PMID: 31209944 DOI: 10.1002/humu.23844] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 05/31/2019] [Accepted: 06/09/2019] [Indexed: 12/20/2022]
Abstract
We report four unrelated children with homozygous loss-of-function variants in TASP1 and an overlapping phenotype comprising developmental delay with hypotonia and microcephaly, feeding difficulties with failure-to-thrive, recurrent respiratory infections, cardiovascular malformations, cryptorchidism, happy demeanor, and distinctive facial features. Two children had a homozygous founder deletion encompassing exons 5-11 of TASP1, the third had a homozygous missense variant, c.701 C>T (p.Thr234Met), affecting the active site of the encoded enzyme, and the fourth had a homozygous nonsense variant, c.199 C>T (p.Arg67*). TASP1 encodes taspase 1 (TASP1), which is responsible for cleaving, thus activating, the lysine methyltransferases KMT2A and KMT2D, which are essential for histone methylation and transcription regulation. The consistency of the phenotype, the critical biological function of TASP1, the deleterious nature of the TASP1 variants, and the overlapping features with Wiedemann-Steiner and Kabuki syndromes respectively caused by pathogenic variants in KMT2A and KMT2D all support that TASP1 is a disease-related gene.
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Affiliation(s)
- Jehan Suleiman
- Division of Neurology, Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates.,Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Korbinian M Riedhammer
- Institute of Human Genetics, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.,Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany.,Department of Nephrology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | | | | | | | - Mirjana Gusic
- Institute of Human Genetics, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.,Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany
| | | | - Hessa S Alsaif
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Maha Abdulrahim
- Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Nabil N Moghrabi
- Molecular Diagnostic Laboratory, Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Manal Nicolas-Jilwan
- Division of Neuroradiology, Department of Radiology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Moeenaldeen AlSayed
- Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Weimin Bi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.,Baylor Genetics, Houston, Texas
| | | | - Fowzan S Alkuraya
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.,Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Ayman W El-Hattab
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Genetics Clinics, KidsHeart Medical Center, Abu Dhabi, United Arab Emirates
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