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Tomikawa C. Pseudouridine Modifications in Transfer RNA and tRNA Pseudouridine Synthases. J Mol Biol 2025:169183. [PMID: 40382211 DOI: 10.1016/j.jmb.2025.169183] [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: 12/16/2024] [Revised: 04/02/2025] [Accepted: 04/28/2025] [Indexed: 05/20/2025]
Abstract
Among the various modifications found in transfer RNAs, pseudouridine occurs the most frequently in all organisms and is also found in other RNA species including ribosomal, messenger, small nuclear, small nucleolar, and transfer-messenger RNA. Since the first gene encoding a tRNA pseudouridine synthase (truA) was discovered in 1978, many pseudouridine synthases have been identified, some of which are specific for one site in tRNA, while others act at multiple sites. Furthermore, some enzymes catalyze pseudouridine modification of not only tRNA but also ribosomal RNA and small nuclear RNA or messenger RNA. The functions of pseudouridine in tRNA are diverse, from contributing to the stabilization of tRNA structure to having an essential role in accurate protein synthesis (deficiency induces a frameshift in some cases). Some pseudouridine synthases also function as RNA chaperones. In this review, I summarize the reaction mechanism and functions of pseudouridine synthases with reference to the six pseudouridine synthase families, including similarities and variations in domain structures, motifs, and target uracil bases. I also characterize individual enzymes and highlight recently revealed links between pseudouridine/pseudouridine synthases and viral infections and human diseases.
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Affiliation(s)
- Chie Tomikawa
- Department of Materials Science and Biotechnology, Graduate School of Science and Engineering, Ehime University, 3 Bunkyo-cho, Matsuyama, Ehime 790-8577, Japan.
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2
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Jia S, Yu X, Deng N, Zheng C, Ju M, Wang F, Zhang Y, Gao Z, Li Y, Zhou H, Li K. Deciphering the pseudouridine nucleobase modification in human diseases: From molecular mechanisms to clinical perspectives. Clin Transl Med 2025; 15:e70190. [PMID: 39834094 PMCID: PMC11746961 DOI: 10.1002/ctm2.70190] [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: 09/26/2024] [Revised: 12/10/2024] [Accepted: 01/08/2025] [Indexed: 01/22/2025] Open
Abstract
RNA pseudouridylation, a dynamic and reversible post-transcriptional modification found in diverse RNA species, is crucial for various biological processes, including tRNA homeostasis, tRNA transport, translation initiation regulation, pre-mRNA splicing, enhancement of mRNA translation, and translational fidelity. Disruption of pseudouridylation impairs cellular homeostasis, contributing to pathological alterations. Recent studies have highlighted its regulatory role in human diseases, particularly in tumourigenesis. Cellular stresses trigger RNA pseudouridylation in organisms, suggesting that pseudouridylation-mediated epigenetic reprogramming is essential for maintaining cellular viability and responding to stress. This review examines the regulatory mechanisms and pathological implications of pseudouridylation in human diseases, with a focus on its involvement in tumourigenesis. Additionally, it explores the therapeutic potential of targeting pseudouridylation, presenting novel strategies for disease treatment. HIGHLIGHTS: Methods to detect pseudouridine were introduced from classic mass spectrometry-based methods to newer approaches such as nanopore-based technologies and BID sequencing, each with its advantages and limitations. RNA pseudouridylation is crucial for various biological processes, including tRNA homeostasis, tRNA transport, translation initiation regulation, pre-mRNA splicing, enhancement of mRNA translation, and translational fidelity. Increased pseudouridylation is frequently associated with tumour initiation, progression, and poor prognosis, whereas its reduction is predominantly implicated in non-tumour diseases. A comprehensive understanding of the inducing factors for RNA pseudouridylation will be essential for elucidating its role in diseases. Such insights can provide robust evidence for how pseudouridylation influences disease progression and offer new avenues for therapeutic strategies targeting pseudouridylation dysregulation. The therapeutic potential of RNA pseudouridylation in diseases is enormous, including inhibitors targeting pseudouridine synthases, the application of RNA pseudouridylation in RNA therapeutics, and its role as a biological marker.
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Affiliation(s)
- Shiheng Jia
- Department of Surgical Oncology and General SurgeryThe First Hospital of China Medical UniversityShenyangLiaoningChina
| | - Xue Yu
- Department of Surgical Oncology and General SurgeryThe First Hospital of China Medical UniversityShenyangLiaoningChina
| | - Na Deng
- Department of HematologyThe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoningChina
| | - Chen Zheng
- Department of Surgical Oncology and General SurgeryThe First Hospital of China Medical UniversityShenyangLiaoningChina
- Department of AnesthesiologyThe First Hospital of China Medical UniversityShenyangLiaoningChina
| | - Mingguang Ju
- Department of Surgical Oncology and General SurgeryThe First Hospital of China Medical UniversityShenyangLiaoningChina
| | - Fanglin Wang
- Department of Surgical Oncology and General SurgeryThe First Hospital of China Medical UniversityShenyangLiaoningChina
| | - Yixiao Zhang
- Department of Surgical Oncology and General SurgeryThe First Hospital of China Medical UniversityShenyangLiaoningChina
| | - Ziming Gao
- Department of Surgical Oncology and General SurgeryThe First Hospital of China Medical UniversityShenyangLiaoningChina
| | - Yanshu Li
- Department of Cell BiologyKey Laboratory of Cell BiologyNational Health Commission of the PRC and Key Laboratory of Medical Cell BiologyMinistry of Education of the PRCChina Medical UniversityShenyangLiaoningChina
| | - Heng Zhou
- Department of Surgical Oncology and General SurgeryThe First Hospital of China Medical UniversityShenyangLiaoningChina
- Department of AnesthesiologyThe First Hospital of China Medical UniversityShenyangLiaoningChina
- Key Laboratory of Molecular Pathology and Epidemiology of Gastric Cancer in Liaoning Education DepartmentThe First Hospital of China Medical UniversityShenyangLiaoningChina
| | - Kai Li
- Department of Surgical Oncology and General SurgeryThe First Hospital of China Medical UniversityShenyangLiaoningChina
- Key Laboratory of Molecular Pathology and Epidemiology of Gastric Cancer in Liaoning Education DepartmentThe First Hospital of China Medical UniversityShenyangLiaoningChina
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3
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Ghosh S, Nguyen MT, Choi HE, Stahl M, Kühn AL, Van der Auwera S, Grabe HJ, Völzke H, Homuth G, Myers SA, Hogaboam CM, Noth I, Martinez FJ, Petsko GA, Glimcher LH. RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening. Nat Commun 2024; 15:7138. [PMID: 39164231 PMCID: PMC11335878 DOI: 10.1038/s41467-024-51336-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 08/02/2024] [Indexed: 08/22/2024] Open
Abstract
Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.
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Affiliation(s)
- Shrestha Ghosh
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
- Department of Immunology, Harvard Medical School, Boston, MA, USA.
| | - Mileena T Nguyen
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Yale University, New Haven, CT, USA
| | - Ha Eun Choi
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Maximilian Stahl
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Annemarie Luise Kühn
- Department for Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
| | - Sandra Van der Auwera
- Department for Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
- German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany
| | - Hans J Grabe
- Department for Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
- German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany
| | - Georg Homuth
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | | | - Cory M Hogaboam
- Women's Guild Lung Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Imre Noth
- Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA
| | - Fernando J Martinez
- Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Gregory A Petsko
- Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Laurie H Glimcher
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
- Department of Immunology, Harvard Medical School, Boston, MA, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
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Villa A, William WN, Hanna GJ. Cancer Precursor Syndromes and Their Detection in the Head and Neck. Hematol Oncol Clin North Am 2024; 38:813-830. [PMID: 38705773 DOI: 10.1016/j.hoc.2024.04.001] [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] [Indexed: 05/07/2024]
Abstract
This article explores the multifaceted landscape of oral cancer precursor syndromes. Hereditary disorders like dyskeratosis congenita and Fanconi anemia increase the risk of malignancy. Oral potentially malignant disorders, notably leukoplakia, are discussed as precursors influenced by genetic and immunologic facets. Molecular insights delve into genetic mutations, allelic imbalances, and immune modulation as key players in precancerous progression, suggesting potential therapeutic targets. The article navigates the controversial terrain of management strategies of leukoplakia, encompassing surgical resection, chemoprevention, and immune modulation, while emphasizing the ongoing challenges in developing effective, evidence-based preventive approaches.
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Affiliation(s)
- Alessandro Villa
- Oral Medicine, Oral Oncology and Dentistry, Miami Cancer Institute, Baptist Health South Florida, 8900 N. Kendall Drive. Miami, FL 33176, USA; Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - William N William
- Thoracic Oncology Program, Grupo Oncoclínicas Grupo Oncoclínicas, Av. Pres. Juscelino Kubitschek, 510, 2º andar, São Paulo, São Paulo 04543-906, Brazil
| | - Glenn J Hanna
- Department of Medical Oncology, Center for Head & Neck Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Dana Building, Room 2-140. Boston, MA 02215, USA.
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5
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Jalan A, Jayasree PJ, Karemore P, Narayan KP, Khandelia P. Decoding the 'Fifth' Nucleotide: Impact of RNA Pseudouridylation on Gene Expression and Human Disease. Mol Biotechnol 2024; 66:1581-1598. [PMID: 37341888 DOI: 10.1007/s12033-023-00792-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 06/08/2023] [Indexed: 06/22/2023]
Abstract
Cellular RNAs, both coding and noncoding are adorned by > 100 chemical modifications, which impact various facets of RNA metabolism and gene expression. Very often derailments in these modifications are associated with a plethora of human diseases. One of the most oldest of such modification is pseudouridylation of RNA, wherein uridine is converted to a pseudouridine (Ψ) via an isomerization reaction. When discovered, Ψ was referred to as the 'fifth nucleotide' and is chemically distinct from uridine and any other known nucleotides. Experimental evidence accumulated over the past six decades, coupled together with the recent technological advances in pseudouridine detection, suggest the presence of pseudouridine on messenger RNA, as well as on diverse classes of non-coding RNA in human cells. RNA pseudouridylation has widespread effects on cellular RNA metabolism and gene expression, primarily via stabilizing RNA conformations and destabilizing interactions with RNA-binding proteins. However, much remains to be understood about the RNA targets and their recognition by the pseudouridylation machinery, the regulation of RNA pseudouridylation, and its crosstalk with other RNA modifications and gene regulatory processes. In this review, we summarize the mechanism and molecular machinery involved in depositing pseudouridine on target RNAs, molecular functions of RNA pseudouridylation, tools to detect pseudouridines, the role of RNA pseudouridylation in human diseases like cancer, and finally, the potential of pseudouridine to serve as a biomarker and as an attractive therapeutic target.
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Affiliation(s)
- Abhishek Jalan
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal-Malkajgiri District, Telangana, 500078, India
| | - P J Jayasree
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal-Malkajgiri District, Telangana, 500078, India
| | - Pragati Karemore
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal-Malkajgiri District, Telangana, 500078, India
| | - Kumar Pranav Narayan
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal-Malkajgiri District, Telangana, 500078, India
| | - Piyush Khandelia
- Department of Biological Sciences, Birla Institute of Technology and Science, Pilani - Hyderabad Campus, Jawahar Nagar, Kapra Mandal, Medchal-Malkajgiri District, Telangana, 500078, India.
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6
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Savage SA. Telomere length and cancer risk: finding Goldilocks. Biogerontology 2024; 25:265-278. [PMID: 38109000 DOI: 10.1007/s10522-023-10080-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 11/13/2023] [Indexed: 12/19/2023]
Abstract
Telomeres are the nucleoprotein complex at chromosome ends essential in genomic stability. Baseline telomere length (TL) is determined by rare and common germline genetic variants but shortens with age and is susceptible to certain environmental exposures. Cellular senescence or apoptosis are normally triggered when telomeres reach a critically short length, but cancer cells overcome these protective mechanisms and continue to divide despite chromosomal instability. Rare germline variants in telomere maintenance genes cause exceedingly short telomeres for age (< 1st percentile) and the telomere biology disorders, which are associated with elevated risks of bone marrow failure, myelodysplastic syndrome, acute myeloid leukemia, and squamous cell carcinoma of the head/neck and anogenital regions. Long telomeres due to rare germline variants in the same or different telomere maintenance genes are associated with elevated risks of other cancers, such as chronic lymphocytic leukemia or sarcoma. Early epidemiology studies of TL in the general population lacked reproducibility but new methods, including creation of a TL polygenic score using common variants, have found longer telomeres associated with excess risks of renal cell carcinoma, glioma, lung cancer, and others. It has become clear that when it comes to TL and cancer etiology, not too short, not too long, but "just right" telomeres are important in minimizing cancer risk.
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Affiliation(s)
- Sharon A Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, 6E456, Bethesda, MD, 20892-6772, USA.
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Lasho T, Patnaik MM. Adaptive and Maladaptive Clonal Hematopoiesis in Telomere Biology Disorders. Curr Hematol Malig Rep 2024; 19:35-44. [PMID: 38095828 DOI: 10.1007/s11899-023-00719-2] [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] [Accepted: 11/24/2023] [Indexed: 01/30/2024]
Abstract
PURPOSE OF REVIEW Telomere biology disorders (TBDs) are germline-inherited conditions characterized by reduction in telomerase function, accelerated shortening of telomeres, predisposition to organ-failure syndromes, and increased risk of neoplasms, especially myeloid malignancies. In normal cells, critically short telomeres trigger apoptosis and/or cellular senescence. However, the evolutionary mechanism by which TBD-related telomerase-deficient cells can overcome this fitness constraint remains elusive. RECENT FINDINGS Preliminary data suggests the existence of adaptive somatic mosaic states characterized by variants in TBD-related genes and maladaptive somatic mosaic states that attempt to overcome hematopoietic fitness constraints by alternative methods leading to clonal hematopoiesis. TBDs are both rare and highly heterogeneous in presentation, and the association of TBD with malignant transformation is unclear. Understanding the clonal complexity and mechanisms behind TBD-associated molecular signatures that lead to somatic adaptation in the setting of defective hematopoiesis will help inform therapy and treatment for this set of diseases.
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Affiliation(s)
- Terra Lasho
- Division of Hematology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN, 55905, USA
| | - Mrinal M Patnaik
- Division of Hematology, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN, 55905, USA.
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8
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Qin J, Garus A, Autexier C. The C-terminal extension of dyskerin is a dyskeratosis congenita mutational hotspot that modulates interaction with telomerase RNA and subcellular localization. Hum Mol Genet 2024; 33:318-332. [PMID: 37879098 PMCID: PMC10840380 DOI: 10.1093/hmg/ddad180] [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: 08/24/2023] [Revised: 10/09/2023] [Accepted: 10/20/2023] [Indexed: 10/27/2023] Open
Abstract
Dyskerin is a component of the human telomerase complex and is involved in stabilizing the human telomerase RNA (hTR). Many mutations in the DKC1 gene encoding dyskerin are found in X-linked dyskeratosis congenita (X-DC), a premature aging disorder and other related diseases. The C-terminal extension (CTE) of dyskerin contributes to its interaction with the molecular chaperone SHQ1 during the early stage of telomerase biogenesis. Disease mutations in this region were proposed to disrupt dyskerin-SHQ1 interaction and destabilize dyskerin, reducing hTR levels indirectly. However, biochemical evidence supporting this hypothesis is still lacking. In addition, the effects of many CTE disease mutations on hTR have not been examined. In this study, we tested eight dyskerin CTE variants and showed that they failed to maintain hTR levels. These mutants showed slightly reduced but not abolished interaction with SHQ1, and caused defective binding to hTR. Deletion of the CTE further reduced binding to hTR, and perturbed localization of dyskerin to the Cajal bodies and the nucleolus, and the interaction with TCAB1 as well as GAR1. Our findings suggest impaired dyskerin-hTR interaction in cells as a previously overlooked mechanism through which dyskerin CTE mutations cause X-DC and related telomere syndromes.
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Affiliation(s)
- Jian Qin
- Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montreal, Quebec, QC H3A 0C7, Canada
- Lady Davis Institute, Jewish General Hospital, 3755 Chem, de la Côte-Sainte-Catherine, Montréal, QC H3T 1E2, Canada
| | - Alexandre Garus
- Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montreal, Quebec, QC H3A 0C7, Canada
- Lady Davis Institute, Jewish General Hospital, 3755 Chem, de la Côte-Sainte-Catherine, Montréal, QC H3T 1E2, Canada
| | - Chantal Autexier
- Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montreal, Quebec, QC H3A 0C7, Canada
- Lady Davis Institute, Jewish General Hospital, 3755 Chem, de la Côte-Sainte-Catherine, Montréal, QC H3T 1E2, Canada
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9
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Liao P, Yan B, Wang C, Lei P. Telomeres: Dysfunction, Maintenance, Aging and Cancer. Aging Dis 2023; 15:2595-2631. [PMID: 38270117 PMCID: PMC11567242 DOI: 10.14336/ad.2023.1128] [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: 10/17/2023] [Accepted: 11/28/2023] [Indexed: 01/26/2024] Open
Abstract
Aging has emerged at the forefront of scientific research due to the growing social and economic costs associated with the growing aging global population. The defining features of aging involve a variety of molecular processes and cellular systems, which are interconnected and collaboratively contribute to the aging process. Herein, we analyze how telomere dysfunction potentially amplifies or accelerates the molecular and biochemical mechanisms underpinning each feature of aging and contributes to the emergence of age-associated illnesses, including cancer and neurodegeneration, via the perspective of telomere biology. Furthermore, the recently identified novel mechanistic actions for telomere maintenance offer a fresh viewpoint and approach to the management of telomeres and associated disorders. Telomeres and the defining features of aging are intimately related, which has implications for therapeutic and preventive approaches to slow aging and reduce the prevalence of age-related disorders.
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Affiliation(s)
- Pan Liao
- The School of Medicine, Nankai University, Tianjin, China.
- Haihe Laboratory of Cell Ecosystem, Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Bo Yan
- Haihe Laboratory of Cell Ecosystem, Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Conglin Wang
- Haihe Laboratory of Cell Ecosystem, Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China.
| | - Ping Lei
- The School of Medicine, Nankai University, Tianjin, China.
- Haihe Laboratory of Cell Ecosystem, Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China.
- Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China.
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10
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Farsi Z, Allahyari Fard N. The identification of key genes and pathways in glioblastoma by bioinformatics analysis. Mol Cell Oncol 2023; 10:2246657. [PMID: 37593751 PMCID: PMC10431734 DOI: 10.1080/23723556.2023.2246657] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 08/07/2023] [Accepted: 08/07/2023] [Indexed: 08/19/2023]
Abstract
GBM is the most common and aggressive type of brain tumor. It is classified as a grade IV tumor by the WHO, the highest grade. Prognosis is generally poor, with most patients surviving only about a year. Only 5% of patients survive longer than 5 years. Understanding the molecular mechanisms that drive GBM progression is critical for developing better diagnostic and treatment strategies. Identifying key genes involved in GBM pathogenesis is essential to fully understand the disease and develop targeted therapies. In this study two datasets, GSE108474 and GSE50161, were obtained from the Gene Expression Omnibus (GEO) to compare gene expression between GBM and normal samples. Differentially expressed genes (DEGs) were identified and analyzed. To construct a protein-protein interaction (PPI) network of the commonly up-regulated and down-regulated genes, the STRING 11.5 and Cytoscape 3.9.1 were utilized. Key genes were identified through this network analysis. The GEPIA database was used to confirm the expression levels of these key genes and their association with survival. Functional and pathway enrichment analyses on the DEGs were conducted using the Enrichr server. In total, 698 DEGs were identified, consisting of 377 up-regulated genes and 318 down-regulated genes. Within the PPI network, 11 key up-regulated genes and 13 key down-regulated genes associated with GBM were identified. NOTCH1, TOP2A, CD44, PTPRC, CDK4, HNRNPU, and PDGFRA were found to be important targets for potential drug design against GBM. Additionally, functional enrichment analysis revealed the significant impact of Epstein-Barr virus (EBV), Cell Cycle, and P53 signaling pathways on GBM.
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Affiliation(s)
- Zahra Farsi
- Department of Biology, Noor-Dnaesh Institute of Higher Education, Esfahan, Iran
| | - Najaf Allahyari Fard
- Department of Systems Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
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11
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Chabronova A, van den Akker G, Housmans BAC, Caron MMJ, Cremers A, Surtel DAM, Peffers MJ, van Rhijn LW, Marchand V, Motorin Y, Welting TJM. Depletion of SNORA33 Abolishes ψ of 28S-U4966 and Affects the Ribosome Translational Apparatus. Int J Mol Sci 2023; 24:12578. [PMID: 37628759 PMCID: PMC10454564 DOI: 10.3390/ijms241612578] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/04/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Eukaryotic ribosomes are complex molecular nanomachines translating genetic information from mRNAs into proteins. There is natural heterogeneity in ribosome composition. The pseudouridylation (ψ) of ribosomal RNAs (rRNAs) is one of the key sources of ribosome heterogeneity. Nevertheless, the functional consequences of ψ-based ribosome heterogeneity and its relevance for human disease are yet to be understood. Using HydraPsiSeq and a chronic disease model of non-osteoarthritic primary human articular chondrocytes exposed to osteoarthritic synovial fluid, we demonstrated that the disease microenvironment is capable of instigating site-specific changes in rRNA ψ profiles. To investigate one of the identified differential rRNA ψ sites (28S-ψ4966), we generated SNORA22 and SNORA33 KO SW1353 cell pools using LentiCRISPRv2/Cas9 and evaluated the ribosome translational capacity by 35S-Met/Cys incorporation, assessed the mode of translation initiation and ribosomal fidelity using dual luciferase reporters, and assessed cellular and ribosomal proteomes by LC-MS/MS. We uncovered that the depletion of SNORA33, but not SNORA22, reduced 28S-ψ4966 levels. The resulting loss of 28S-ψ4966 affected ribosomal protein composition and function and led to specific changes in the cellular proteome. Overall, our pioneering findings demonstrate that cells dynamically respond to disease-relevant changes in their environment by altering their rRNA pseudouridylation profiles, with consequences for ribosome function and the cellular proteome relevant to human disease.
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Affiliation(s)
- Alzbeta Chabronova
- Laboratory for Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University, 6229 HX Maastricht, The Netherlands; (A.C.); (B.A.C.H.)
| | - Guus van den Akker
- Laboratory for Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University, 6229 HX Maastricht, The Netherlands; (A.C.); (B.A.C.H.)
| | - Bas A. C. Housmans
- Laboratory for Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University, 6229 HX Maastricht, The Netherlands; (A.C.); (B.A.C.H.)
| | - Marjolein M. J. Caron
- Laboratory for Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University, 6229 HX Maastricht, The Netherlands; (A.C.); (B.A.C.H.)
| | - Andy Cremers
- Laboratory for Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University, 6229 HX Maastricht, The Netherlands; (A.C.); (B.A.C.H.)
| | - Don A. M. Surtel
- Laboratory for Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University, 6229 HX Maastricht, The Netherlands; (A.C.); (B.A.C.H.)
| | - Mandy J. Peffers
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L8 7TX, UK
| | - Lodewijk W. van Rhijn
- Laboratory for Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University, 6229 HX Maastricht, The Netherlands; (A.C.); (B.A.C.H.)
| | - Virginie Marchand
- UAR2008 IBSLor CNRS-INSERM-Université de Lorraine, F54000 Nancy, France
| | - Yuri Motorin
- UAR2008 IBSLor CNRS-INSERM-Université de Lorraine, F54000 Nancy, France
- UMR7365 IMOPA, CNRS-Université de Lorraine, F54000 Nancy, France
| | - Tim J. M. Welting
- Laboratory for Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University, 6229 HX Maastricht, The Netherlands; (A.C.); (B.A.C.H.)
- Laboratory for Experimental Orthopedics, Department of Orthopedic Surgery, Maastricht University Medical Center+ (MUMC+), 6229 HX Maastricht, The Netherlands
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12
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Breznak SM, Peng Y, Deng L, Kotb NM, Flamholz Z, Rapisarda IT, Martin ET, LaBarge KA, Fabris D, Gavis ER, Rangan P. H/ACA snRNP-dependent ribosome biogenesis regulates translation of polyglutamine proteins. SCIENCE ADVANCES 2023; 9:eade5492. [PMID: 37343092 PMCID: PMC10284551 DOI: 10.1126/sciadv.ade5492] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 05/17/2023] [Indexed: 06/23/2023]
Abstract
Stem cells in many systems, including Drosophila germline stem cells (GSCs), increase ribosome biogenesis and translation during terminal differentiation. Here, we show that the H/ACA small nuclear ribonucleoprotein (snRNP) complex that promotes pseudouridylation of ribosomal RNA (rRNA) and ribosome biogenesis is required for oocyte specification. Reducing ribosome levels during differentiation decreased the translation of a subset of messenger RNAs that are enriched for CAG trinucleotide repeats and encode polyglutamine-containing proteins, including differentiation factors such as RNA-binding Fox protein 1. Moreover, ribosomes were enriched at CAG repeats within transcripts during oogenesis. Increasing target of rapamycin (TOR) activity to elevate ribosome levels in H/ACA snRNP complex-depleted germlines suppressed the GSC differentiation defects, whereas germlines treated with the TOR inhibitor rapamycin had reduced levels of polyglutamine-containing proteins. Thus, ribosome biogenesis and ribosome levels can control stem cell differentiation via selective translation of CAG repeat-containing transcripts.
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Affiliation(s)
- Shane M. Breznak
- Department of Biological Sciences, RNA Institute, University at Albany, 1400 Washington Avenue, LSRB 2033D, Albany, NY 12222, USA
| | - Yingshi Peng
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Limin Deng
- Department of Biological Sciences, RNA Institute, University at Albany, 1400 Washington Avenue, LSRB 2033D, Albany, NY 12222, USA
- Department of Chemistry, University of Connecticut, 55N Eagleville Rd, Storrs, CT 06269, USA
| | - Noor M. Kotb
- Department of Biological Sciences, RNA Institute, University at Albany, 1400 Washington Avenue, LSRB 2033D, Albany, NY 12222, USA
- Department of Biomedical Sciences, University at Albany School of Public Health, Albany, NY 12144, USA
| | - Zachary Flamholz
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Ian T. Rapisarda
- Department of Biological Sciences, RNA Institute, University at Albany, 1400 Washington Avenue, LSRB 2033D, Albany, NY 12222, USA
- Lake Erie College of Osteopathic Medicine, College of Medicine, 1858 W Grandview Blvd, Erie, PA 16509, USA
| | - Elliot T. Martin
- Department of Biological Sciences, RNA Institute, University at Albany, 1400 Washington Avenue, LSRB 2033D, Albany, NY 12222, USA
| | - Kara A. LaBarge
- Department of Biological Sciences, RNA Institute, University at Albany, 1400 Washington Avenue, LSRB 2033D, Albany, NY 12222, USA
| | - Dan Fabris
- Department of Biological Sciences, RNA Institute, University at Albany, 1400 Washington Avenue, LSRB 2033D, Albany, NY 12222, USA
- Department of Chemistry, University of Connecticut, 55N Eagleville Rd, Storrs, CT 06269, USA
| | - Elizabeth R. Gavis
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Prashanth Rangan
- Department of Biological Sciences, RNA Institute, University at Albany, 1400 Washington Avenue, LSRB 2033D, Albany, NY 12222, USA
- Black Family Stem Cell Institute, Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA
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13
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Tokunaga M, Imamura T. Emerging concepts involving inhibitory and activating RNA functionalization towards the understanding of microcephaly phenotypes and brain diseases in humans. Front Cell Dev Biol 2023; 11:1168072. [PMID: 37408531 PMCID: PMC10318543 DOI: 10.3389/fcell.2023.1168072] [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: 02/17/2023] [Accepted: 06/12/2023] [Indexed: 07/07/2023] Open
Abstract
Microcephaly is characterized as a small head circumference, and is often accompanied by developmental disorders. Several candidate risk genes for this disease have been described, and mutations in non-coding regions are occasionally found in patients with microcephaly. Various non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), SINEUPs, telomerase RNA component (TERC), and promoter-associated lncRNAs (pancRNAs) are now being characterized. These ncRNAs regulate gene expression, enzyme activity, telomere length, and chromatin structure through RNA binding proteins (RBPs)-RNA interaction. Elucidating the potential roles of ncRNA-protein coordination in microcephaly pathogenesis might contribute to its prevention or recovery. Here, we introduce several syndromes whose clinical features include microcephaly. In particular, we focus on syndromes for which ncRNAs or genes that interact with ncRNAs may play roles. We discuss the possibility that the huge ncRNA field will provide possible new therapeutic approaches for microcephaly and also reveal clues about the factors enabling the evolutionary acquisition of the human-specific "large brain."
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14
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Barozzi C, Zacchini F, Corradini AG, Morara M, Serra M, De Sanctis V, Bertorelli R, Dassi E, Montanaro L. Alterations of ribosomal RNA pseudouridylation in human breast cancer. NAR Cancer 2023; 5:zcad026. [PMID: 37260601 PMCID: PMC10227372 DOI: 10.1093/narcan/zcad026] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 05/12/2023] [Accepted: 05/17/2023] [Indexed: 06/02/2023] Open
Abstract
RNA modifications are key regulatory factors for several biological and pathological processes. They are abundantly represented on ribosomal RNA (rRNA), where they contribute to regulate ribosomal function in mRNA translation. Altered RNA modification pathways have been linked to tumorigenesis as well as to other human diseases. In this study we quantitatively evaluated the site-specific pseudouridylation pattern in rRNA in breast cancer samples exploiting the RBS-Seq technique involving RNA bisulfite treatment coupled with a new NGS approach. We found a wide variability among patients at different sites. The most dysregulated positions in tumors turned out to be hypermodified with respect to a reference RNA. As for 2'O-methylation level of rRNA modification, we detected variable and stable pseudouridine sites, with the most stable sites being the most evolutionary conserved. We also observed that pseudouridylation levels at specific sites are related to some clinical and bio-pathological tumor features and they are able to distinguish different patient clusters. This study is the first example of the contribution that newly available high-throughput approaches for site specific pseudouridine detection can provide to the understanding of the intrinsic ribosomal changes occurring in human tumors.
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Affiliation(s)
- Chiara Barozzi
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna I-40138, Italy
- Centre for Applied Biomedical Research – CRBA, University of Bologna, Sant’Orsola Hospital, Bologna I-40138, Italy
| | - Federico Zacchini
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna I-40138, Italy
- Centre for Applied Biomedical Research – CRBA, University of Bologna, Sant’Orsola Hospital, Bologna I-40138, Italy
| | - Angelo Gianluca Corradini
- Unit of Pathology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, I-40138 Bologna, Italy
| | - Monica Morara
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna I-40138, Italy
- Departmental Program in Laboratory Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, I-40138 Bologna, Italy
| | - Margherita Serra
- Unit of Breast Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, I-40138 Bologna, Italy
| | - Veronica De Sanctis
- Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Povo (TN) I-38123, Italy
| | - Roberto Bertorelli
- Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Povo (TN) I-38123, Italy
| | - Erik Dassi
- Department of Cellular, Computational and Integrative Biology - CIBIO, University of Trento, Povo (TN) I-38123, Italy
| | - Lorenzo Montanaro
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum - University of Bologna, Bologna I-40138, Italy
- Departmental Program in Laboratory Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, I-40138 Bologna, Italy
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15
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O’Connor TE, Shaw R, Madero-Marroquin R, Roloff GW. Clinical considerations at the intersection of hematopoietic cell transplantation and hereditary hematopoietic malignancy. Front Oncol 2023; 13:1180439. [PMID: 37251919 PMCID: PMC10213438 DOI: 10.3389/fonc.2023.1180439] [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: 03/06/2023] [Accepted: 04/28/2023] [Indexed: 05/31/2023] Open
Abstract
In recent years, advances in genetics and the integration of clinical-grade next-generation sequencing (NGS) assays into patient care have facilitated broader recognition of hereditary hematopoietic malignancy (HHM) among clinicians, in addition to the identification and characterization of novel HHM syndromes. Studies on genetic risk distribution within affected families and unique considerations of HHM biology represent exciting areas of translational research. More recently, data are now emerging pertaining to unique aspects of clinical management of malignancies arising in the context of pathogenic germline mutations, with particular emphasis on chemotherapy responsiveness. In this article, we explore considerations surrounding allogeneic transplantation in the context of HHMs. We review pre- and post-transplant patient implications, including genetic testing donor selection and donor-derived malignancies. Additionally, we consider the limited data that exist regarding the use of transplantation in HHMs and safeguards that might be pursued to mitigate transplant-related toxicities.
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Affiliation(s)
- Timothy E. O’Connor
- Department of Medicine, Loyola University Medical Center, Maywood, IL, United States
| | - Reid Shaw
- Department of Medicine, Loyola University Medical Center, Maywood, IL, United States
| | | | - Gregory W. Roloff
- Section of Hematology/Oncology, The University of Chicago, Chicago, IL, United States
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16
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Keszthelyi TM, Tory K. The importance of pseudouridylation: human disorders related to the fifth nucleoside. Biol Futur 2023:10.1007/s42977-023-00158-3. [PMID: 37000312 DOI: 10.1007/s42977-023-00158-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 03/09/2023] [Indexed: 04/01/2023]
Abstract
Pseudouridylation is one of the most abundant RNA modifications in eukaryotes, making pseudouridine known as the "fifth nucleoside." This highly conserved alteration affects all non-coding and coding RNA types. Its role and importance have been increasingly widely researched, especially considering that its absence or damage leads to serious hereditary diseases. Here, we summarize the human genetic disorders described to date that are related to the participants of the pseudouridylation process.
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Affiliation(s)
| | - Kálmán Tory
- Department of Pediatrics, Semmelweis University, Budapest, Hungary
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17
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Khakzad M, Shahbazi Z, Naderi M, Karimipoor M. A de novo TINF2, R282C Mutation in a Case of Dyskeratosis Congenital Founded by Next-Generation Sequencing. IRANIAN BIOMEDICAL JOURNAL 2023; 27:146-51. [PMID: 37070599 PMCID: PMC10314759 DOI: 10.61186/ibj.3783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 10/26/2022] [Indexed: 12/17/2023]
Abstract
Background Dyskeratosis congenita (DC), an inherited and rare disease prevalent in males, is clinically manifested by reticulate hyperpigmentation, nail dystrophy, and leukoplakia. DC is associated with the increased risk of malignancy and other potentially lethal complications such as bone marrow failure, as well as lung and liver diseases. Mutations in 19 genes were found to be correlated with DC. Herein, we report a 12-year-old boy carrying a de novo mutation in TINF2 gene. Methods Whole exome sequencing (WES) was performed on DNA sample of the proband, and the variant was investigated in the family by Sanger sequencing. Population and bioinformatics analysis were performed. Results The NM_ 001099274.3(TINF2): c.844C>T (p.Arg282Cys) mutation was found by WES. Conclusion There was no history of the disease in the family, and the variant was classified as a de novo mutation.
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Affiliation(s)
- Motahareh Khakzad
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Zahra Shahbazi
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Majid Naderi
- Ali Ebne Abitaleb Hospital, School of Medicine, University of Medical Sciences, Zahedan, Iran
| | - Morteza Karimipoor
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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18
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Revy P, Kannengiesser C, Bertuch AA. Genetics of human telomere biology disorders. Nat Rev Genet 2023; 24:86-108. [PMID: 36151328 DOI: 10.1038/s41576-022-00527-z] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/11/2022] [Indexed: 01/24/2023]
Abstract
Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that prevent the activation of DNA damage response and repair pathways. Numerous factors localize at telomeres to regulate their length, structure and function, to avert replicative senescence or genome instability and cell death. In humans, Mendelian defects in several of these factors can result in abnormally short or dysfunctional telomeres, causing a group of rare heterogeneous premature-ageing diseases, termed telomeropathies, short-telomere syndromes or telomere biology disorders (TBDs). Here, we review the TBD-causing genes identified so far and describe their main functions associated with telomere biology. We present molecular aspects of TBDs, including genetic anticipation, phenocopy, incomplete penetrance and somatic genetic rescue, which underlie the complexity of these diseases. We also discuss the implications of phenotypic and genetic features of TBDs on fundamental aspects related to human telomere biology, ageing and cancer, as well as on diagnostic, therapeutic and clinical approaches.
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Affiliation(s)
- Patrick Revy
- INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue Nationale contre le Cancer, Paris, France.
- Université Paris Cité, Imagine Institute, Paris, France.
| | - Caroline Kannengiesser
- APHP Service de Génétique, Hôpital Bichat, Paris, France
- Inserm U1152, Université Paris Cité, Paris, France
| | - Alison A Bertuch
- Departments of Paediatrics and Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA
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19
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Borziak K, Finkelstein J. X-linked genetic risk factors that promote autoimmunity and dampen remyelination are associated with multiple sclerosis susceptibility. Mult Scler Relat Disord 2022; 66:104065. [PMID: 35905688 DOI: 10.1016/j.msard.2022.104065] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/14/2022] [Accepted: 07/17/2022] [Indexed: 01/21/2023]
Abstract
BACKGROUND Multiple sclerosis (MS) is a chronic neurodegenerative disease, which has a strong genetic component and is more prevalent in women. MS is caused by an autoimmunity initiated inflammatory response which leads to axon demyelination, followed by axon loss, plaque formation and neurodegeneration. The goal of this article was to explore X-linked genetic factors that are associated with MS susceptibility. METHODS Using UK Biobank microarray, we analyzed the prevalence of alleles on the X chromosome to identify variants potentially involved in MS. Overall, 488,225 patients across 18,857 markers were analyzed using PLINK. RESULTS Our results identify 20 SNPs that are significantly more abundant in persons with MS. The genes associated with these SNPs belong to immunity (LAMP2, AVPR2, MTMR8, F8, BCOR, PORCN, and ELF4) and remyelination (NSDHL, HS6ST2, RBM10, TAZ, and AR) pathways that are potentially of great significance for understanding the onset and progression of multiple sclerosis. We further identified a significant 20-fold increase in incidence of MS cases in women with co-occurrences of SNPs associated with myelination and immunity functions. CONCLUSIONS Our analysis provides novel insights into the roles of X-linked genes in the onset and presentation of multiple sclerosis, identifying 20 SNPs in 14 genes involved primarily in immunity and myelination functions that are significantly more abundant in persons with MS. Our co-occurrence analysis suggests that concurrent disruption of both myelination and immune systems significantly increases the risk of MS onset in women.
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Affiliation(s)
- Kirill Borziak
- Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 United States.
| | - Joseph Finkelstein
- Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029 United States
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20
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Nagpal N, Tai AK, Nandakumar J, Agarwal S. Domain specific mutations in dyskerin disrupt 3' end processing of scaRNA13. Nucleic Acids Res 2022; 50:9413-9425. [PMID: 36018809 PMCID: PMC9458449 DOI: 10.1093/nar/gkac706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 07/27/2022] [Accepted: 08/10/2022] [Indexed: 12/24/2022] Open
Abstract
Mutations in DKC1 (encoding dyskerin) cause telomere diseases including dyskeratosis congenita (DC) by decreasing steady-state levels of TERC, the non-coding RNA component of telomerase. How DKC1 mutations variably impact numerous other snoRNAs remains unclear, which is a barrier to understanding disease mechanisms in DC beyond impaired telomere maintenance. Here, using DC patient iPSCs, we show that mutations in the dyskerin N-terminal extension domain (NTE) dysregulate scaRNA13. In iPSCs carrying the del37L NTE mutation or engineered to carry NTE mutations via CRISPR/Cas9, but not in those with C-terminal mutations, we found scaRNA13 transcripts with aberrant 3' extensions, as seen when the exoribonuclease PARN is mutated in DC. Biogenesis of scaRNA13 was rescued by repair of the del37L DKC1 mutation by genome-editing, or genetic or pharmacological inactivation of the polymerase PAPD5, which counteracts PARN. Inspection of the human telomerase cryo-EM structure revealed that in addition to mediating intermolecular dyskerin interactions, the NTE interacts with terminal residues of the associated snoRNA, indicating a role for this domain in 3' end definition. Our results provide mechanistic insights into the interplay of dyskerin and the PARN/PAPD5 axis in the biogenesis and accumulation of snoRNAs beyond TERC, broadening our understanding of ncRNA dysregulation in human diseases.
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Affiliation(s)
- Neha Nagpal
- Division of Hematology/Oncology and Stem Cell Program, Boston Children's Hospital; Pediatric Oncology, Dana-Farber Cancer Institute; Harvard Stem Cell Institute; Department of Pediatrics, Harvard Medical School; Manton Center for Orphan Disease Research; Harvard Initiative in RNA Medicine; Boston, MA, USA
| | - Albert K Tai
- Department of Immunology, Tufts University School of Medicine, Boston, MA, USA
- Data Intensive Studies Center, Tufts University, Medford, MA, USA
| | - Jayakrishnan Nandakumar
- Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Suneet Agarwal
- To whom correspondence should be addressed. Tel: +1 617 919 4610; Fax: +1 617 919 3359;
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21
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Han JH, Ryan G, Guy A, Liu L, Quinodoz M, Helbling I, Lai-Cheong JE, Genomics England Research Consortium, Barwell J, Folcher M, McGrath JA, Moss C, Rivolta C. Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder. Hum Mol Genet 2022; 31:1970-1978. [PMID: 34999892 PMCID: PMC9239743 DOI: 10.1093/hmg/ddab368] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 11/18/2021] [Accepted: 12/13/2021] [Indexed: 11/12/2022] Open
Abstract
In the framework of the UK 100 000 Genomes Project, we investigated the genetic origin of a previously undescribed recessive dermatological condition, which we named LIPHAK (LTV1-associated Inflammatory Poikiloderma with Hair abnormalities and Acral Keratoses), in four affected individuals from two UK families of Pakistani and Indian origins, respectively. Our analysis showed that only one gene, LTV1, carried rare biallelic variants that were shared in all affected individuals, and specifically they bore the NM_032860.5:c.503A > G, p.(Asn168Ser) change, found homozygously in all of them. In addition, high-resolution homozygosity mapping revealed the presence of a small 652-kb stretch on chromosome 6, encompassing LTV1, that was haploidentical and common to all affected individuals. The c.503A > G variant was predicted by in silico tools to affect the correct splicing of LTV1's exon 5. Minigene-driven splicing assays in HEK293T cells and in a skin sample from one of the patients confirmed that this variant was indeed responsible for the creation of a new donor splice site, resulting in aberrant splicing and in a premature termination codon in exon 6 of this gene. LTV1 encodes one of the ribosome biogenesis factors that promote the assembly of the small (40S) ribosomal subunit. In yeast, defects in LTV1 alter the export of nascent ribosomal subunits to the cytoplasm; however, the role of this gene in human pathology is unknown to date. Our data suggest that LIPHAK could be a previously unrecognized ribosomopathy.
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Affiliation(s)
- Ji Hoon Han
- Institute of Molecular and Clinical Ophthalmology Basel (IOB), 4031 Basel, Switzerland
- Department of Ophthalmology, University of Basel, 4031 Basel, Switzerland
| | - Gavin Ryan
- West Midlands Regional Genetics Laboratory, Central and South Genomic Laboratory Hub, Birmingham B15 2TG, UK
| | - Alyson Guy
- Viapath, St Thomas' Hospital, London SE1 7EH, UK
| | - Lu Liu
- Viapath, St Thomas' Hospital, London SE1 7EH, UK
| | - Mathieu Quinodoz
- Institute of Molecular and Clinical Ophthalmology Basel (IOB), 4031 Basel, Switzerland
- Department of Ophthalmology, University of Basel, 4031 Basel, Switzerland
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
| | - Ingrid Helbling
- Department of Dermatology, University Hospitals of Leicester NHS Trust, Leicester LE1 5WW, UK
| | | | | | - Julian Barwell
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
- Department of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester LE1 5WW, UK
| | - Marc Folcher
- Institute of Molecular and Clinical Ophthalmology Basel (IOB), 4031 Basel, Switzerland
- Department of Ophthalmology, University of Basel, 4031 Basel, Switzerland
| | - John A McGrath
- NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London SE1 9RT, UK
- St John's Institute of Dermatology, King's College London (Guy's campus), London SE1 9RT, UK
| | - Celia Moss
- Department of Paediatric Dermatology, Birmingham Women’s and Children’s Hospital NHS FT, Birmingham B4 6NH, UK
- College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - Carlo Rivolta
- Institute of Molecular and Clinical Ophthalmology Basel (IOB), 4031 Basel, Switzerland
- Department of Ophthalmology, University of Basel, 4031 Basel, Switzerland
- Department of Genetics and Genome Biology, University of Leicester, Leicester LE1 7RH, UK
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22
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Guo Q, Zhang P, Ying W, Wang Y, Zhu J, Li G, Wang H, Wang X, Lei C, Zhou W, Sun J, Wu B. Intron retention by a novel intronic mutation in DKC1 gene caused recurrent still birth and early death in a Chinese family. Mol Genet Genomic Med 2022; 10:e1934. [PMID: 35384376 PMCID: PMC9184655 DOI: 10.1002/mgg3.1934] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 02/09/2022] [Accepted: 03/14/2022] [Indexed: 11/06/2022] Open
Abstract
Background DKC1, the dyskerin encoding gene, functions in telomerase activity and telomere maintenance. DKC1 mutations cause a multisystem disease, dyskeratosis congenita (DC), which is associated with immunodeficiency and bone marrow failure. Methods In this research, we reported a novel intronic mutation of DKC1 causing dyskerin functional loss in a Chinese family. Whole exome sequence (WES) of the proband and validation by sanger sequencing help us identify a pathogenic DKC1 mutation. Minigene splicing assays were performed to evaluate functional change of DKC1. Results A pathogenic DKC1 intronic mutation(c.84 + 7A > G) was identified in the proband, which was inherited from heterozygous mother and not reported before. We detected the novel transcript with a 7 bp intron retention through minigene splicing assay. The newly spliced transcript is so short that would be degraded by nonsense‐mediated mRNA decay in vitro and we infer that the novel DKC1 mutation would influences normal physiological function of dyskerin. Conclusions Our study identified a novel intronic mutation, which expands the spectrum of pathogenic DKC1 gene mutations and can be used in molecular diagnosis. The mutant allele was transmitted to the next generation with high frequency in the family and causes still birth or early death.
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Affiliation(s)
- Qiufang Guo
- Center of Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.,Berry Genomics Co., Beijing, China
| | - Ping Zhang
- Center of Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Wenjing Ying
- Department of Allergy and Clinical Immunology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Yaqiong Wang
- Center of Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Jitao Zhu
- Center of Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Gang Li
- Center of Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Huijun Wang
- Center of Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Xiaochuan Wang
- Center of Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Caixia Lei
- Prenatal Diagnosis Center, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Wenhao Zhou
- Center of Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Jinqiao Sun
- Department of Allergy and Clinical Immunology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
| | - Bingbing Wu
- Center of Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China
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Vagher J, Gammon A, Kohlmann W, Jeter J. Non-Melanoma Skin Cancers and Other Cutaneous Manifestations in Bone Marrow Failure Syndromes and Rare DNA Repair Disorders. Front Oncol 2022; 12:837059. [PMID: 35359366 PMCID: PMC8960432 DOI: 10.3389/fonc.2022.837059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/17/2022] [Indexed: 11/17/2022] Open
Abstract
Although most non-melanoma skin cancers are felt to be sporadic in origin, these tumors do play a role in several cancer predisposition syndromes. The manifestations of skin cancers in these hereditary populations can include diagnosis at extremely early ages and/or multiple primary cancers, as well as tumors at less common sites. Awareness of baseline skin cancer risks for these individuals is important, particularly in the setting of treatments that may compromise the immune system and further increase risk of cutaneous malignancies. Additionally, diagnosis of these disorders and management of non-cutaneous manifestations of these diseases have profound implications for both the patient and their family. This review highlights the current literature on the diagnosis, features, and non-melanoma skin cancer risks associated with lesser-known cancer predisposition syndromes, including bone marrow failure disorders, genomic instability disorders, and base excision repair disorders.
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Affiliation(s)
- Jennie Vagher
- Family Cancer Assessment Clinic, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Amanda Gammon
- Family Cancer Assessment Clinic, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Wendy Kohlmann
- Family Cancer Assessment Clinic, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Joanne Jeter
- Family Cancer Assessment Clinic, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
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24
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Martinez NM, Su A, Burns MC, Nussbacher JK, Schaening C, Sathe S, Yeo GW, Gilbert WV. Pseudouridine synthases modify human pre-mRNA co-transcriptionally and affect pre-mRNA processing. Mol Cell 2022; 82:645-659.e9. [PMID: 35051350 PMCID: PMC8859966 DOI: 10.1016/j.molcel.2021.12.023] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 11/04/2021] [Accepted: 12/17/2021] [Indexed: 02/05/2023]
Abstract
Pseudouridine is a modified nucleotide that is prevalent in human mRNAs and is dynamically regulated. Here, we investigate when in their life cycle mRNAs become pseudouridylated to illuminate the potential regulatory functions of endogenous mRNA pseudouridylation. Using single-nucleotide resolution pseudouridine profiling on chromatin-associated RNA from human cells, we identified pseudouridines in nascent pre-mRNA at locations associated with alternatively spliced regions, enriched near splice sites, and overlapping hundreds of binding sites for RNA-binding proteins. In vitro splicing assays establish a direct effect of individual endogenous pre-mRNA pseudouridines on splicing efficiency. We validate hundreds of pre-mRNA sites as direct targets of distinct pseudouridine synthases and show that PUS1, PUS7, and RPUSD4-three pre-mRNA-modifying pseudouridine synthases with tissue-specific expression-control widespread changes in alternative pre-mRNA splicing and 3' end processing. Our results establish a vast potential for cotranscriptional pre-mRNA pseudouridylation to regulate human gene expression via alternative pre-mRNA processing.
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Affiliation(s)
- Nicole M Martinez
- Yale School of Medicine, Department of Molecular Biophysics & Biochemistry, New Haven, CT 06520, USA
| | - Amanda Su
- Yale School of Medicine, Department of Molecular Biophysics & Biochemistry, New Haven, CT 06520, USA
| | - Margaret C Burns
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92037, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92037, USA
| | - Julia K Nussbacher
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92037, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92037, USA
| | - Cassandra Schaening
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Shashank Sathe
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92037, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92037, USA
| | - Gene W Yeo
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Stem Cell Program, University of California, San Diego, La Jolla, CA 92037, USA; Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
| | - Wendy V Gilbert
- Yale School of Medicine, Department of Molecular Biophysics & Biochemistry, New Haven, CT 06520, USA.
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25
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Abstract
Cellular RNAs in all three kingdoms of life are modified with diverse chemical modifications. These chemical modifications expand the topological repertoire of RNAs, and fine-tune their functions. Ribosomal RNA in yeast contains more than 100 chemically modified residues in the functionally crucial and evolutionary conserved regions. The chemical modifications in the rRNA are of three types-methylation of the ribose sugars at the C2-positionAbstract (Nm), isomerization of uridines to pseudouridines (Ψ), and base modifications such as (methylation (mN), acetylation (acN), and aminocarboxypropylation (acpN)). The modifications profile of the yeast rRNA has been recently completed, providing an excellent platform to analyze the function of these modifications in RNA metabolism and in cellular physiology. Remarkably, majority of the rRNA modifications and the enzymatic machineries discovered in yeast are highly conserved in eukaryotes including humans. Mutations in factors involved in rRNA modification are linked to several rare severe human diseases (e.g., X-linked Dyskeratosis congenita, the Bowen-Conradi syndrome and the William-Beuren disease). In this chapter, we summarize all rRNA modifications and the corresponding enzymatic machineries of the budding yeast.
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Affiliation(s)
- Sunny Sharma
- Department of Cell Biology and Neurosciences, Rutgers University, Piscataway, NJ, USA.
| | - Karl-Dieter Entian
- Institute of Molecular Biosciences, J.W. Goethe University, Frankfurt/M., Germany.
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26
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Wang L, Li J, Xiong Q, Zhou YA, Li P, Wu C. Case Report: A Missense Mutation in Dyskeratosis Congenita 1 Leads to a Benign Form of Dyskeratosis Congenita Syndrome With the Mucocutaneous Triad. Front Pediatr 2022; 10:834268. [PMID: 35463902 PMCID: PMC9019361 DOI: 10.3389/fped.2022.834268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 02/25/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Dyskeratosis congenita (DC) is a rare inheritable disorder characterized by bone marrow failure and mucocutaneous triad (reticular skin pigmentation, nail dystrophy, and oral leukoplakia). Dyskeratosis congenita 1 (DKC1) is responsible for 4.6% of the DC with an X-linked inheritance pattern. Almost 70 DKC1 variations causing DC have been reported in the Human Gene Mutation Database. RESULTS Here we described a 14-year-old boy in a Chinese family with a phenotype of abnormal skin pigmentation on the neck, oral leukoplakia, and nail dysplasia in his hands and feet. Genetic analysis and sequencing revealed hemizygosity for a recurrent missense mutation c.1156G > A (p.Ala386Thr) in DKC1 gene. The heterozygous mutation (c.1156G > A) from his mother and wild-type sequence from his father were obtained in the same site of DKC1. This mutation was determined as disease causing based on silico software, but the pathological phenotypes of the proband were milder than previously reported at this position (HGMDCM060959). Homology modeling revealed that the altered amino acid was located near the PUA domain, which might affect the affinity for RNA binding. CONCLUSION This DKC1 mutation (c.1156G > A, p.Ala386Thr) was first reported in a Chinese family with mucocutaneous triad phenotype. Our study reveals the pathogenesis of DKC1 c.1156G > A mutation to DC with a benign phenotype, which expands the disease variation database, the understanding of genotype-phenotype correlations, and facilitates the clinical diagnosis of DC in China.
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Affiliation(s)
- Liqing Wang
- The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, Shanxi University, Taiyuan, China.,The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institute of Biomedical Sciences, Shanxi University, Taiyuan, China
| | - Jianwei Li
- Bluttransfusion, The Second Hospital, Shanxi Medical University, Taiyuan, China
| | - Qiuhong Xiong
- The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, Shanxi University, Taiyuan, China.,The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institute of Biomedical Sciences, Shanxi University, Taiyuan, China
| | - Yong-An Zhou
- Bluttransfusion, The Second Hospital, Shanxi Medical University, Taiyuan, China
| | - Ping Li
- The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, Shanxi University, Taiyuan, China.,The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institute of Biomedical Sciences, Shanxi University, Taiyuan, China
| | - Changxin Wu
- The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, Shanxi University, Taiyuan, China.,The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Institute of Biomedical Sciences, Shanxi University, Taiyuan, China
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27
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Kawano-Dourado L, Glassberg MK, Assayag D, Borie R, Johannson KA. Sex and gender in interstitial lung diseases. Eur Respir Rev 2021; 30:210105. [PMID: 34789464 PMCID: PMC9489177 DOI: 10.1183/16000617.0105-2021] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/01/2021] [Indexed: 12/14/2022] Open
Abstract
Sex and gender differences influence key domains of research, lung health, healthcare access and healthcare delivery. In interstitial lung diseases (ILDs), mouse models of pulmonary fibrosis are clearly influenced by sex hormones. Additionally, short telomeres, a biomarker of telomere regulation gene mutations, are impacted by sex, while heritability unexplained by genetic variation may be attributable to gendered environmental factors that drive epigenetic control. Diseases like idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, occupational ILDs, connective tissue-associated ILDs and lymphangioleiomyomatosis have different prevalence and prognosis between men and women. These differences arise from a complex interplay between biological sex and sociocultural gender influencing genetics, epigenomic modifiers, hormones, immune function, response to treatment and interaction with healthcare systems. Much work remains to be done to systematically integrate sex and gender analysis into relevant domains of science and clinical care in ILD, from strategic considerations for establishing research priorities to guidelines for establishing best clinical practices. Accounting for sex and gender in ILD is essential to the practice of individualised, patient-centred medicine.
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Affiliation(s)
- Leticia Kawano-Dourado
- HCor Research Institute, Hospital do Coracao, Sao Paulo, Brazil
- Pulmonary Division, Heart Institute (InCor), University of Sao Paulo, Sao Paulo, Brazil
- INSERM 1152, University of Paris, Paris, France
| | - Marilyn K Glassberg
- Pulmonary, Critical Care, and Sleep Medicine Division, Dept of Medicine, University of Arizona College of Medicine, Phoenix, AZ, USA
| | | | - Raphaël Borie
- Pulmonary Division, Hospital Bichat, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France
| | - Kerri A Johannson
- Depts of Medicine and Community Health Sciences, University of Calgary, Calgary, AB, Canada
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
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28
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Garus A, Autexier C. Dyskerin: an essential pseudouridine synthase with multifaceted roles in ribosome biogenesis, splicing, and telomere maintenance. RNA (NEW YORK, N.Y.) 2021; 27:1441-1458. [PMID: 34556550 PMCID: PMC8594475 DOI: 10.1261/rna.078953.121] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Dyskerin and its homologs are ancient and conserved enzymes that catalyze the most common post-transcriptional modification found in cells, pseudouridylation. The resulting pseudouridines provide stability to RNA molecules and regulate ribosome biogenesis and splicing events. Dyskerin does not act independently-it is the core component of a protein heterotetramer, which associates with RNAs that contain the H/ACA motif. The variety of H/ACA RNAs that guide the function of this ribonucleoprotein (RNP) complex highlights the diversity of cellular processes in which dyskerin participates. When associated with small nucleolar (sno) RNAs, it regulates ribosomal (r) RNAs and ribosome biogenesis. By interacting with small Cajal body (sca) RNAs, it targets small nuclear (sn) RNAs to regulate pre-mRNA splicing. As a component of the telomerase holoenzyme, dyskerin binds to the telomerase RNA to modulate telomere maintenance. In a disease context, dyskerin malfunction can result in multiple detrimental phenotypes. Mutations in DKC1, the gene that encodes dyskerin, cause the premature aging syndrome X-linked dyskeratosis congenita (X-DC), a still incurable disorder that typically leads to bone marrow failure. In this review, we present the classical and most recent findings on this essential protein, discussing the evolutionary, structural, and functional aspects of dyskerin and the H/ACA RNP. The latest research underscores the role that dyskerin plays in the regulation of gene expression, translation efficiency, and telomere maintenance, along with the impacts that defective dyskerin has on aging, cell proliferation, haematopoietic potential, and cancer.
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Affiliation(s)
- Alexandre Garus
- Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, H3A 0C7, Canada
- Jewish General Hospital, Lady Davis Institute, Montreal, Quebec, H3T 1E2, Canada
| | - Chantal Autexier
- Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, H3A 0C7, Canada
- Jewish General Hospital, Lady Davis Institute, Montreal, Quebec, H3T 1E2, Canada
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29
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Borie R, Renzoni E. Pulmonary fibrosis associated with telomere-related gene mutations: A complex inheritance. Respirology 2021; 26:1098-1100. [PMID: 34617352 DOI: 10.1111/resp.14168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 09/29/2021] [Indexed: 10/20/2022]
Affiliation(s)
- Raphael Borie
- Service de Pneumologie, Centre constitutif du centre de référence, des Maladies Pulmonaires Rares, Hôpital Bichat, APHP, INSERM, Université Paris Diderot, Paris, France
| | - Elisabetta Renzoni
- Interstitial Lung Disease Unit, Royal Brompton and Harefield Clinical Group, Guy's and St Thomas' NHS Foundation Trust, London, UK.,Margaret Turner Warwick Centre for Fibrosing Lung Diseases, NHLI, Imperial College, London, UK
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30
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Quantitative profiling of pseudouridylation dynamics in native RNAs with nanopore sequencing. Nat Biotechnol 2021; 39:1278-1291. [PMID: 33986546 DOI: 10.1038/s41587-021-00915-6] [Citation(s) in RCA: 182] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 04/06/2021] [Indexed: 01/23/2023]
Abstract
Nanopore RNA sequencing shows promise as a method for discriminating and identifying different RNA modifications in native RNA. Expanding on the ability of nanopore sequencing to detect N6-methyladenosine, we show that other modifications, in particular pseudouridine (Ψ) and 2'-O-methylation (Nm), also result in characteristic base-calling 'error' signatures in the nanopore data. Focusing on Ψ modification sites, we detected known and uncovered previously unreported Ψ sites in mRNAs, non-coding RNAs and rRNAs, including a Pus4-dependent Ψ modification in yeast mitochondrial rRNA. To explore the dynamics of pseudouridylation, we treated yeast cells with oxidative, cold and heat stresses and detected heat-sensitive Ψ-modified sites in small nuclear RNAs, small nucleolar RNAs and mRNAs. Finally, we developed a software, nanoRMS, that estimates per-site modification stoichiometries by identifying single-molecule reads with altered current intensity and trace profiles. This work demonstrates that Nm and Ψ RNA modifications can be detected in cellular RNAs and that their modification stoichiometry can be quantified by nanopore sequencing of native RNA.
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31
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Arthur JW, Pickett HA, Barbaro PM, Kilo T, Vasireddy RS, Beilharz TH, Powell DR, Hackett EL, Bennetts B, Curtin JA, Jones K, Christodoulou J, Reddel RR, Teo J, Bryan TM. A novel cause of DKC1-related bone marrow failure: Partial deletion of the 3' untranslated region. EJHAEM 2021; 2:157-166. [PMID: 35845273 PMCID: PMC9175968 DOI: 10.1002/jha2.165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 01/03/2021] [Accepted: 01/07/2021] [Indexed: 12/11/2022]
Abstract
Telomere biology disorders (TBDs), including dyskeratosis congenita (DC), are a group of rare inherited diseases characterized by very short telomeres. Mutations in the components of the enzyme telomerase can lead to insufficient telomere maintenance in hematopoietic stem cells, resulting in the bone marrow failure that is characteristic of these disorders. While an increasing number of genes are being linked to TBDs, the causative mutation remains unidentified in 30-40% of patients with DC. There is therefore a need for whole genome sequencing (WGS) in these families to identify novel genes, or mutations in regulatory regions of known disease-causing genes. Here we describe a family in which a partial deletion of the 3' untranslated region (3' UTR) of DKC1, encoding the protein dyskerin, was identified by WGS, despite being missed by whole exome sequencing. The deletion segregated with disease across the family and resulted in reduced levels of DKC1 mRNA in the proband. We demonstrate that the DKC1 3' UTR contains two polyadenylation signals, both of which were removed by this deletion, likely causing mRNA instability. Consistent with the major function of dyskerin in stabilization of the RNA subunit of telomerase, hTR, the level of hTR was also reduced in the proband, providing a molecular basis for his very short telomeres. This study demonstrates that the terminal region of the 3' UTR of the DKC1 gene is essential for gene function and illustrates the importance of analyzing regulatory regions of the genome for molecular diagnosis of inherited disease.
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Affiliation(s)
- Jonathan W. Arthur
- Children's Medical Research InstituteFaculty of Medicine and Health, University of SydneyWestmeadNew South WalesAustralia
| | - Hilda A. Pickett
- Children's Medical Research InstituteFaculty of Medicine and Health, University of SydneyWestmeadNew South WalesAustralia
| | - Pasquale M. Barbaro
- Children's Medical Research InstituteFaculty of Medicine and Health, University of SydneyWestmeadNew South WalesAustralia
| | - Tatjana Kilo
- Haematology DepartmentChildren's Hospital at WestmeadWestmeadNew South WalesAustralia
| | - Raja S. Vasireddy
- Haematology DepartmentChildren's Hospital at WestmeadWestmeadNew South WalesAustralia
| | - Traude H. Beilharz
- Monash Biomedicine Discovery InstituteDepartment of Biochemistry and Molecular Biology, Monash UniversityClaytonVictoriaAustralia
| | - David R. Powell
- Monash Bioinformatics PlatformMonash UniversityClaytonVictoriaAustralia
| | - Emma L. Hackett
- Department of Molecular GeneticsChildren's Hospital WestmeadWestmeadNew South WalesAustralia
| | - Bruce Bennetts
- Department of Molecular GeneticsChildren's Hospital WestmeadWestmeadNew South WalesAustralia
- Disciplines of Genetic Medicine and Child and Adolescent Health, Faculty of Medicine and HealthUniversity of SydneyWestmeadNew South WalesAustralia
| | - Julie A. Curtin
- Haematology DepartmentChildren's Hospital at WestmeadWestmeadNew South WalesAustralia
| | - Kristi Jones
- Disciplines of Genetic Medicine and Child and Adolescent Health, Faculty of Medicine and HealthUniversity of SydneyWestmeadNew South WalesAustralia
- Department of Clinical GeneticsChildren's Hospital WestmeadWestmeadNew South WalesAustralia
| | - John Christodoulou
- Disciplines of Genetic Medicine and Child and Adolescent Health, Faculty of Medicine and HealthUniversity of SydneyWestmeadNew South WalesAustralia
- Murdoch Children's Research Institute and Department of PaediatricsMelbourne Medical SchoolParkvilleVictoriaAustralia
| | - Roger R. Reddel
- Children's Medical Research InstituteFaculty of Medicine and Health, University of SydneyWestmeadNew South WalesAustralia
| | - Juliana Teo
- Haematology DepartmentChildren's Hospital at WestmeadWestmeadNew South WalesAustralia
| | - Tracy M. Bryan
- Children's Medical Research InstituteFaculty of Medicine and Health, University of SydneyWestmeadNew South WalesAustralia
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32
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Loss of Pseudouridine Synthases in the RluA Family Causes Hypersensitive Nociception in Drosophila. G3-GENES GENOMES GENETICS 2020; 10:4425-4438. [PMID: 33028630 PMCID: PMC7718762 DOI: 10.1534/g3.120.401767] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Nociceptive neurons of Drosophila melanogaster larvae are characterized by highly branched dendritic processes whose proper morphogenesis relies on a large number of RNA-binding proteins. Post-transcriptional regulation of RNA in these dendrites has been found to play an important role in their function. Here, we investigate the neuronal functions of two putative RNA modification genes, RluA-1 and RluA-2, which are predicted to encode pseudouridine synthases. RluA-1 is specifically expressed in larval sensory neurons while RluA-2 expression is ubiquitous. Nociceptor-specific RNAi knockdown of RluA-1 caused hypersensitive nociception phenotypes, which were recapitulated with genetic null alleles. These were rescued with genomic duplication and nociceptor-specific expression of UAS- RluA-1 -cDNA As with RluA-1, RluA-2 loss of function mutants also displayed hyperalgesia. Interestingly, nociceptor neuron dendrites showed a hyperbranched morphology in the RluA-1 mutants. The latter may be a cause or a consequence of heightened sensitivity in mutant nociception behaviors.
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33
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DKC1 Overexpression Induces a More Aggressive Cellular Behavior and Increases Intrinsic Ribosomal Activity in Immortalized Mammary Gland Cells. Cancers (Basel) 2020; 12:cancers12123512. [PMID: 33255756 PMCID: PMC7760958 DOI: 10.3390/cancers12123512] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/23/2020] [Accepted: 11/23/2020] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Dyskerin is a nucleolar protein involved in the modification and processing of ribosomal RNA and in the stabilization of the telomerase RNA component. In several human tumors, including breast cancer, dyskerin overexpression is found related to patients’ worse prognosis. Our aim was to study this phenomenon at the molecular and cellular levels. We firstly confirmed the correlation between high dyskerin expression with patients’ shorter survival. Then, through the generation of cellular models of increased dyskerin expression, we found that increasing dyskerin levels conferred a more aggressive phenotype and increased intrinsic ribosomal activity only in cells derived from normal breast epithelium. Our study provides evidence on the prognostic and bio-pathological relevance of the overexpression of dyskerin in breast carcinoma. A possible mechanistic explanation of the effects of dyskerin overexpression, involving specific ribosomal RNA modification and consequent increased ribosomal activity, is also provided. Abstract Dyskerin is a nucleolar protein involved in the small nucleolar RNA (snoRNA)-guided pseudouridylation of specific uridines on ribosomal RNA (rRNA), and in the stabilization of the telomerase RNA component (hTR). Loss of function mutations in DKC1 causes X-linked dyskeratosis congenita, which is characterized by a failure of proliferating tissues and increased susceptibility to cancer. However, several tumors show dyskerin overexpression. We observed that patients with primary breast cancers with high dyskerin levels are more frequently characterized by shorter survival rates and positive lymph node status than those with tumors with a lower dyskerin expression. To functionally characterize the effects of high dyskerin expression, we generated stably overexpressing DKC1 models finding that increased dyskerin levels conferred a more aggressive cellular phenotype in untransformed immortalized MCF10A cells. Contextually, DKC1 overexpression led to an upregulation of some snoRNAs, including SNORA67 and a significantly increased U1445 modification on 18S rRNA, the known target of SNORA67. Lastly, we found that dyskerin overexpression strongly enhanced the synthetic activity of ribosomes increasing translational efficiency in MCF10A. Altogether, our results indicate that dyskerin may sustain the neoplastic phenotype from an early stage in breast cancer endowing ribosomes with an augmented translation efficiency.
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Gaysinskaya V, Stanley SE, Adam S, Armanios M. Synonymous Mutation in DKC1 Causes Telomerase RNA Insufficiency Manifesting as Familial Pulmonary Fibrosis. Chest 2020; 158:2449-2457. [PMID: 32710892 DOI: 10.1016/j.chest.2020.07.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 07/11/2020] [Accepted: 07/13/2020] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is the most common of short telomere phenotypes. Familial clustering of IPF is common, but the genetic basis remains unknown in more than one-half of cases. We identified a 65-year-old man with familial IPF, short telomere length, and low telomerase RNA levels. He was diagnosed with a short telomere syndrome after developing hematologic complications post-lung transplantation, but no mutations were identified in a clinical testing pipeline. RESEARCH QUESTION What is the molecular basis underlying the familial IPF and low telomerase RNA levels in this patient? STUDY DESIGN AND METHODS We analyzed whole-genome sequence data and performed functional molecular studies on cells derived from the patient and his family. RESULTS We identified a previously unreported synonymous variant c.942G>A p.K314K in DKC1, the gene encoding the dyskerin ribonucleoprotein, which is required for telomerase RNA biogenesis. The mutation created a competing de novo exonic splicing enhancer, and the misspliced product was degraded by nonsense-mediated decay causing an overall dyskerin deficiency in mutation carriers. In silico tools identified other rare silent DKC1 variants that warrant functional evaluation if found in patients with short telomere-mediated disease. INTERPRETATION Our data point to silent mutation in telomere maintenance genes as a mechanism of familial pulmonary fibrosis. In contrast to DKC1 missense mutations, which primarily manifest in children as dyskeratosis congenita, hypomorphic mutations affecting dyskerin levels likely have a predilection to presenting in adults as pulmonary fibrosis.
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Affiliation(s)
- Valeriya Gaysinskaya
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD; Telomere Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Susan E Stanley
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD; Telomere Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Soheir Adam
- Department of Medicine, Duke University School of Medicine, Durham, NC
| | - Mary Armanios
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD; Sidney Kimmel Comprehensive Cancer, Johns Hopkins University School of Medicine, Baltimore, MD.
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35
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Abstract
The interstitial lung diseases (ILDs) are a group of progressive disorders characterized by chronic inflammation and/or fibrosis in the lung. While some ILDs can be linked to specific environmental causes (i.e., asbestosis, silicosis), in many individuals, no culprit exposure can be identified; these patients are deemed to have "idiopathic interstitial pneumonia" (IIP). Family history is now recognized as the strongest risk factor for IIP, and IIP cases that run in families comprise a syndrome termed "familial interstitial pneumonia" (FIP). Mutations in more than 10 different genes have been implicated as responsible for disease in FIP families. Diverse ILD clinical phenotypes can be seen within a family, and available evidence suggests underlying genetic risk is the primary determinant of disease outcomes. Together, these FIP studies have provided unique insights into the pathobiology of ILDs, and brought focus on the unique issues that arise in the care of patients with FIP.
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Affiliation(s)
- Jonathan A Kropski
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
- U.S. Department of Veterans Affairs Medical Center, Nashville, Tennessee
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36
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Terada K, Miyake K, Yamaguchi H, Miyake N, Yamanaka K, Kojima S, Ito E, Inokuchi K, Okada T. TERT and TERC mutations detected in cryptic dyskeratosis congenita suppress telomerase activity. Int J Lab Hematol 2020; 42:316-321. [PMID: 32150348 DOI: 10.1111/ijlh.13176] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 01/22/2020] [Accepted: 02/12/2020] [Indexed: 11/28/2022]
Abstract
INTRODUCTION A cryptic form of dyskeratosis congenita (cDKC) has a gradual onset without the characteristic physical findings of DKC. cDKC is distinguished from other forms of bone marrow failure (BMF) through analysis of telomere shortening and gene mutations. Mutations in the telomerase reverse transcriptase (TERT) and telomere RNA component (TERC) genes have been detected in most Japanese cDKC patients. Therefore, we investigated the impact of each TERT and TERC mutation on telomerase activity. METHODS TERT and TERC mutants observed in DKC or cDKC patients were transfected into Saos-2 or VA13+TERT (TERT-expressing VA13 cells) cells to measure telomerase activity. RESULTS Telomerase activity in cells expressing a mutant detected in cDKC patients was significantly lower (P < .0001) than in cells expressing the wild-type genes. In addition, some TERT mutations seen in cDKC (p.P632R, p.T726M) caused weaker (P = .0013) suppression of telomerase activity than others (p.G106W and p.G682D). In contrast, telomerase activity in cells expressing a TERT or TERC mutant detected in DKC patients did not significantly differ from cells expressing the wild-type genes. CONCLUSION These findings suggest that TERT and TERC mutations detected in cDKC patients could potentially contribute to the pathogenesis of cDKC by blocking telomerase activity. However, TERT and TERC mutations detected in DKC patients did not affect telomerase activities, which means studying the telomerase activity of mutants are not always useful for the diagnosis of DKC.
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Affiliation(s)
- Kazuki Terada
- Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.,Department of Hematology, Nippon Medical School, Tokyo, Japan
| | - Koichi Miyake
- Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan
| | | | - Noriko Miyake
- Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan
| | | | - Seiji Kojima
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Etsuro Ito
- Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Koiti Inokuchi
- Department of Hematology, Nippon Medical School, Tokyo, Japan
| | - Takashi Okada
- Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.,Division of Molecular and Medical Genetics, The Institute of Medical Science,The University of Tokyo, Tokyo, Japan
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MacNeil DE, Lambert-Lanteigne P, Autexier C. N-terminal residues of human dyskerin are required for interactions with telomerase RNA that prevent RNA degradation. Nucleic Acids Res 2019; 47:5368-5380. [PMID: 30931479 PMCID: PMC6547437 DOI: 10.1093/nar/gkz233] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 03/19/2019] [Accepted: 03/25/2019] [Indexed: 12/16/2022] Open
Abstract
The telomerase holoenzyme responsible for maintaining telomeres in vertebrates requires many components in vivo, including dyskerin. Dyskerin binds and regulates the accumulation of the human telomerase RNA, hTR, as well as other non-coding RNAs that share the conserved H/ACA box motif. The precise mechanism by which dyskerin controls hTR levels is unknown, but is evidenced by defective hTR accumulation caused by substitutions in dyskerin, that are observed in the X-linked telomere biology disorder dyskeratosis congenita (X-DC). To understand the role of dyskerin in hTR accumulation, we analyzed X-DC substitutions K39E and K43E in the poorly characterized dyskerin N-terminus, and A353V within the canonical RNA binding domain (the PUA). These variants exhibited impaired binding to hTR and polyadenylated hTR species, while interactions with other H/ACA RNAs appear largely unperturbed by the N-terminal substitutions. hTR accumulation and telomerase activity defects of dyskerin-deficient cells were rescued by wildtype dyskerin but not the variants. hTR 3′ extended or polyadenylated species did not accumulate, suggesting hTR precursor degradation occurs upstream of mature complex assembly in the absence of dyskerin binding. Our findings demonstrate that the dyskerin-hTR interaction mediated by PUA and N-terminal residues of dyskerin is crucial to prevent unchecked hTR degradation.
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Affiliation(s)
- Deanna E MacNeil
- Jewish General Hospital of McGill University, Lady Davis Institute, Montreal, Quebec H3T 1E2, Canada.,Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 0C7, Canada
| | - Patrick Lambert-Lanteigne
- Jewish General Hospital of McGill University, Lady Davis Institute, Montreal, Quebec H3T 1E2, Canada
| | - Chantal Autexier
- Jewish General Hospital of McGill University, Lady Davis Institute, Montreal, Quebec H3T 1E2, Canada.,Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 0C7, Canada
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Dyskerin Mutations Present in Dyskeratosis Congenita Patients Increase Oxidative Stress and DNA Damage Signalling in Dictyostelium Discoideum. Cells 2019; 8:cells8111406. [PMID: 31717312 PMCID: PMC6912284 DOI: 10.3390/cells8111406] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/04/2019] [Accepted: 11/05/2019] [Indexed: 12/17/2022] Open
Abstract
Dyskerin is a protein involved in the formation of small nucleolar and small Cajal body ribonucleoproteins. These complexes participate in RNA pseudouridylation and are also components of the telomerase complex required for telomere elongation. Dyskerin mutations cause a rare disease, X-linked dyskeratosis congenita, with no curative treatment. The social amoeba Dictyostelium discoideum contains a gene coding for a dyskerin homologous protein. In this article D. discoideum mutant strains that have mutations corresponding to mutations found in dyskeratosis congenita patients are described. The phenotype of the mutant strains has been studied and no alterations were observed in pseudouridylation activity and telomere structure. Mutant strains showed increased proliferation on liquid culture but reduced growth feeding on bacteria. The results obtained indicated the existence of increased DNA damage response and reactive oxygen species, as also reported in human Dyskeratosis congenita cells and some other disease models. These data, together with the haploid character of D. discoideum vegetative cells, that resemble the genomic structure of the human dyskerin gene, located in the X chromosome, support the conclusion that D. discoideum can be a good model system for the study of this disease.
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39
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Niewisch MR, Savage SA. An update on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol 2019; 12:1037-1052. [PMID: 31478401 DOI: 10.1080/17474086.2019.1662720] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Introduction: Telomere biology disorders (TBDs) encompass a group of illnesses caused by germline mutations in genes regulating telomere maintenance, resulting in very short telomeres. Possible TBD manifestations range from complex multisystem disorders with onset in childhood such as dyskeratosis congenita (DC), Hoyeraal-Hreidarsson syndrome, Revesz syndrome and Coats plus to adults presenting with one or two DC-related features.Areas covered: The discovery of multiple genetic causes and inheritance patterns has led to the recognition of a spectrum of clinical features affecting multiple organ systems. Patients with DC and associated TBDs are at high risk of bone marrow failure, cancer, liver and pulmonary disease. Recently, vascular diseases, including pulmonary arteriovenous malformations and gastrointestinal telangiectasias, have been recognized as additional manifestations. Diagnostics include detection of very short leukocyte telomeres and germline genetic testing. Hematopoietic cell transplantation and lung transplantation are the only current therapeutic modalities but are complicated by numerous comorbidities. This review summarizes the pathophysiology underlying TBDs, associated clinical features, management recommendations and therapeutic options.Expert opinion: Understanding TBDs as complex, multisystem disorders with a heterogenous genetic background and diverse phenotypes, highlights the importance of clinical surveillance and the urgent need to develop new therapeutic strategies to improve health outcomes.
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Affiliation(s)
- Marena R Niewisch
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sharon A Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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40
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Donaires FS, Alves-Paiva RM, Gutierrez-Rodrigues F, da Silva FB, Tellechea MF, Moreira LF, Santana BA, Traina F, Dunbar CE, Winkler T, Calado RT. Telomere dynamics and hematopoietic differentiation of human DKC1-mutant induced pluripotent stem cells. Stem Cell Res 2019; 40:101540. [PMID: 31479877 DOI: 10.1016/j.scr.2019.101540] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 08/08/2019] [Accepted: 08/19/2019] [Indexed: 02/07/2023] Open
Abstract
Telomeropathies are a group of phenotypically heterogeneous diseases molecularly unified by pathogenic mutations in telomere-maintenance genes causing critically short telomeres. X-linked dyskeratosis congenita (DC), the prototypical telomere disease, manifested with ectodermal dysplasia, cancer predisposition, and severe bone marrow failure, is caused by mutations in DKC1, encoding a protein responsible for telomerase holoenzyme complex stability. To investigate the effects of pathogenic DKC1 mutations on telomere repair and hematopoietic development, we derived induced pluripotent stem cells (iPSCs) from fibroblasts of a DC patient carrying the most frequent mutation: DKC1 p.A353V. Telomeres eroded immediately after reprogramming in DKC1-mutant iPSCs but stabilized in later passages. The telomerase activity of mutant iPSCs was comparable to that observed in human embryonic stem cells, and no evidence of alternative lengthening of telomere pathways was detected. Hematopoietic differentiation was carried out in DKC1-mutant iPSC clones that resulted in increased capacity to generate hematopoietic colony-forming units compared to controls. Our study indicates that telomerase-dependent telomere maintenance is defective in pluripotent stem cells harboring DKC1 mutation and unable to elongate telomeres, but sufficient to maintain cell proliferation and self-renewal, as well as to support the primitive hematopoiesis, the program that is recapitulated with our differentiation protocol.
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Affiliation(s)
- Flavia S Donaires
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Raquel M Alves-Paiva
- Department of Medical Imaging, Hematology, and Clinical Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Fernanda Gutierrez-Rodrigues
- Department of Medical Imaging, Hematology, and Clinical Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Fernanda Borges da Silva
- Department of Medical Imaging, Hematology, and Clinical Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Maria Florencia Tellechea
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Lilian Figueiredo Moreira
- Department of Medical Imaging, Hematology, and Clinical Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Barbara A Santana
- Department of Medical Imaging, Hematology, and Clinical Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Fabiola Traina
- Department of Medical Imaging, Hematology, and Clinical Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Cynthia E Dunbar
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Thomas Winkler
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Rodrigo T Calado
- Department of Medical Imaging, Hematology, and Clinical Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
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41
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Watanabe M, Yamamoto G, Fujiyoshi K, Akagi Y, Kakuta M, Nishimura Y, Akagi K. Development of metachronous rectal cancers in a young man with dyskeratosis congenita: a case report. J Med Case Rep 2019; 13:117. [PMID: 31027506 PMCID: PMC6486685 DOI: 10.1186/s13256-019-2044-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Accepted: 03/07/2019] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND DKC1 (dyskerin pseudouridine synthase 1) is a causative gene for X-linked dyskeratosis congenita. Approximately 8% of patients with dyskeratosis congenita have malignancy, but information about the development of malignancy in patients with dyskeratosis congenita is limited. CASE PRESENTATION A young Japanese patient with bone marrow failure developed metachronous rectal adenocarcinomas at the ages of 16 and 18 years. He had no family history of cancer. Microsatellite instability testing with rectal tumor tissue demonstrated low-level microsatellite instability. To clarify whether any cancer susceptibility genes were involved in the development of rectal cancer, RNA sequencing was performed. Cancer-related genes were assessed, and a c.361A>G (p.Ser121Gly) germline variant was detected in DKC1. The same missense variant was previously reported in two patients with dyskeratosis congenita as a pathogenic variant, but those patients did not develop malignancies. CONCLUSIONS Our patient developed rectal cancer at an early age of onset compared with the previously reported typical onset age of patients with dyskeratosis congenita. DKC1 might be involved in predisposition to colorectal cancer in young adulthood; therefore, appropriate surveillance may be considered.
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Affiliation(s)
- Motoko Watanabe
- Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama, 362-0806, Japan
| | - Gou Yamamoto
- Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama, 362-0806, Japan
| | | | - Yoshito Akagi
- Department of Surgery, Kurume University, Fukuoka, Japan
| | - Miho Kakuta
- Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama, 362-0806, Japan
| | - Yoji Nishimura
- Division of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan
| | - Kiwamu Akagi
- Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama, 362-0806, Japan.
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42
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Noronha SA. Aplastic and Hypoplastic Anemias. Pediatr Rev 2018; 39:601-611. [PMID: 30504252 DOI: 10.1542/pir.2017-0250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Suzie A Noronha
- Division of Pediatric Hematology/Oncology, University of Rochester, Rochester, NY
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43
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Aubert M, O'Donohue MF, Lebaron S, Gleizes PE. Pre-Ribosomal RNA Processing in Human Cells: From Mechanisms to Congenital Diseases. Biomolecules 2018; 8:biom8040123. [PMID: 30356013 PMCID: PMC6315592 DOI: 10.3390/biom8040123] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 10/19/2018] [Accepted: 10/19/2018] [Indexed: 12/15/2022] Open
Abstract
Ribosomal RNAs, the most abundant cellular RNA species, have evolved as the structural scaffold and the catalytic center of protein synthesis in every living organism. In eukaryotes, they are produced from a long primary transcript through an intricate sequence of processing steps that include RNA cleavage and folding and nucleotide modification. The mechanisms underlying this process in human cells have long been investigated, but technological advances have accelerated their study in the past decade. In addition, the association of congenital diseases to defects in ribosome synthesis has highlighted the central place of ribosomal RNA maturation in cell physiology regulation and broadened the interest in these mechanisms. Here, we give an overview of the current knowledge of pre-ribosomal RNA processing in human cells in light of recent progress and discuss how dysfunction of this pathway may contribute to the physiopathology of congenital diseases.
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Affiliation(s)
- Maxime Aubert
- Laboratoire de Biologie Moléculaire Eucaryote, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31000 Toulouse, France.
| | - Marie-Françoise O'Donohue
- Laboratoire de Biologie Moléculaire Eucaryote, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31000 Toulouse, France.
| | - Simon Lebaron
- Laboratoire de Biologie Moléculaire Eucaryote, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31000 Toulouse, France.
| | - Pierre-Emmanuel Gleizes
- Laboratoire de Biologie Moléculaire Eucaryote, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31000 Toulouse, France.
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Abstract
Studies of rare and common illnesses have led to remarkable progress in the understanding of the role of telomeres (nucleoprotein complexes at chromosome ends essential for chromosomal integrity) in human disease. Telomere biology disorders encompass a growing spectrum of conditions caused by rare pathogenic germline variants in genes encoding essential aspects of telomere function. Dyskeratosis congenita, a disorder at the severe end of this spectrum, typically presents in childhood with the classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia, accompanied by a very high risk of bone marrow failure, cancer, pulmonary fibrosis, and other medical problems. In contrast, the less severe end of the telomere biology disorder spectrum consists of middle-age or older adults with just one feature typically seen in dyskeratosis congenita, such as pulmonary fibrosis or bone marrow failure. In the common disease realm, large-scale molecular epidemiology studies have discovered novel associations between illnesses, such as cancer, heart disease, and mental health, and both telomere length and common genetic variants in telomere biology genes. This review highlights recent findings of telomere biology in human disease from both the rare and common disease perspectives. Multi-disciplinary collaborations between clinicians, basic scientists, and epidemiologist are essential as we seek to incorporate new telomere biology discoveries to improve health outcomes.
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Affiliation(s)
- Sharon A. Savage
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
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45
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Snetselaar R, van Oosterhout MFM, Grutters JC, van Moorsel CHM. Telomerase Reverse Transcriptase Polymorphism rs2736100: A Balancing Act between Cancer and Non-Cancer Disease, a Meta-Analysis. Front Med (Lausanne) 2018. [PMID: 29536006 PMCID: PMC5835035 DOI: 10.3389/fmed.2018.00041] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The enzyme telomerase reverse transcriptase (TERT) is essential for telomere maintenance. In replicating cells, maintenance of telomere length is important for the preservation of vital genetic information and prevention of genomic instability. A common genetic variant in TERT, rs2736100 C/A, is associated with both telomere length and multiple diseases. Carriage of the C allele is associated with longer telomere length, while carriage of the A allele is associated with shorter telomere length. Furthermore, some diseases have a positive association with the C and some with the A allele. In this study, meta-analyses were performed for two groups of diseases, cancerous diseases, e.g., lung cancer and non-cancerous diseases, e.g., pulmonary fibrosis, using data from genome-wide association studies and case-control studies. In the meta-analysis it was found that cancer positively associated with the C allele (pooled OR 1.16 [95% CI 1.09–1.23]) and non-cancerous diseases negatively associated with the C allele (pooled OR 0.81 [95% CI 0.65–0.99]). This observation illustrates that the ambiguous role of telomere maintenance in disease hinges, at least in part, on a single locus in telomerase genes. The dual role of this single nucleotide polymorphism also emphasizes that therapeutic agents aimed at influencing telomere maintenance should be used with caution.
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Affiliation(s)
- Reinier Snetselaar
- Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, Netherlands
| | - Matthijs F M van Oosterhout
- Interstitial Lung Diseases Center of Excellence, Department of Pathology, St Antonius Hospital, Nieuwegein, Netherlands
| | - Jan C Grutters
- Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, Netherlands.,Division of Heart and Lung, University Medical Center Utrecht, Utrecht, Netherlands
| | - Coline H M van Moorsel
- Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St Antonius Hospital, Nieuwegein, Netherlands.,Division of Heart and Lung, University Medical Center Utrecht, Utrecht, Netherlands
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Liu XX, Pan JF, Zhao QJ, He XH, Pu YB, Han JL, Ma YH, Jiang L. Detecting selection signatures on the X chromosome of the Chinese Debao pony. J Anim Breed Genet 2018; 135:84-92. [PMID: 29345071 DOI: 10.1111/jbg.12314] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 12/12/2017] [Indexed: 12/11/2022]
Abstract
The X chromosome shows a special interaction between demographic factors and genetic variation, and the analysis of X-linked genomic variation can therefore provide insights into the unique effects of demography and selection on the horse genome that cannot be readily detected by autosomal markers. Debao (DB) ponies have experienced intense selective pressure for the development of their small stature (<106 cm at adult height). To identify selective sweeps on the X chromosome of the DB pony, we performed a genome-wide scan of three Chinese horse breeds using an Equine SNP70 BeadChip. Using Yili and Mongolian horses (>134 cm at adult height) as reference groups, both FST and XP-EHH revealed that five regions on the X chromosome were under strong selection, resulting in 95 overlapping genes. Seven of these genes, SMS, PHEX, ACSL4, CHRDL1, CACNA1F, DKC1 and CDKL5, are involved in bone development, growth hormone secretion and fat deposition. The region showing the strongest selection pressure was located at the position of 86.6-87.5 Mb. The subsequent genome-wide association analysis of the adult height of three Chinese horse breeds detected the two most significant SNPs in the same region, and these two SNPs overlapped with the gene CHRDL1. As a member of the bone morphogenetic protein (BMP) superfamily, CHRDL1 antagonizes the function of BMP4 and plays an important role in embryonic bone formation and cartilage generation. Our results provide new insights into the X-linked selection in Chinese Debao pony.
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Affiliation(s)
- X-X Liu
- Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,CAAS-ILRI Joint Laboratory on Livestock and Forage Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - J-F Pan
- Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,CAAS-ILRI Joint Laboratory on Livestock and Forage Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Q-J Zhao
- Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,CAAS-ILRI Joint Laboratory on Livestock and Forage Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - X-H He
- Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,CAAS-ILRI Joint Laboratory on Livestock and Forage Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Y-B Pu
- Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,CAAS-ILRI Joint Laboratory on Livestock and Forage Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - J-L Han
- CAAS-ILRI Joint Laboratory on Livestock and Forage Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,International Livestock Research Institute (ILRI), Nairobi, Kenya
| | - Y-H Ma
- Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,CAAS-ILRI Joint Laboratory on Livestock and Forage Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - L Jiang
- Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China.,CAAS-ILRI Joint Laboratory on Livestock and Forage Genetic Resources, Institute of Animal Science, Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
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47
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Telomeres and Telomerase in Hematopoietic Dysfunction: Prognostic Implications and Pharmacological Interventions. Int J Mol Sci 2017; 18:ijms18112267. [PMID: 29143804 PMCID: PMC5713237 DOI: 10.3390/ijms18112267] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 10/15/2017] [Accepted: 10/24/2017] [Indexed: 12/31/2022] Open
Abstract
Leukocyte telomere length (TL) has been suggested as a marker of biological age in healthy individuals, but can also reflect inherited and acquired hematopoietic dysfunctions or indicate an increased turnover of the hematopoietic stem and progenitor cell compartment. In addition, TL is able to predict the response rate of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (CML), indicates clinical outcomes in chronic lymphocytic leukemia (CLL), and can be used as screening tool for genetic sequencing of selected genes in patients with inherited bone marrow failure syndromes (BMFS). In tumor cells and clonal hematopoietic disorders, telomeres are continuously stabilized by reactivation of telomerase, which can selectively be targeted by telomerase-specific therapy. The use of the telomerase inhibitor Imetelstat in patients with essential thrombocythmia or myelofibrosis as well as the use of dendritic cell-based telomerase vaccination in AML patients with complete remissions are promising examples for anti-telomerase targeted strategies in hematologic malignancies. In contrast, the elevation in telomerase levels through treatment with androgens has become an exciting clinical intervention for patients with BMFS. Here, we review recent developments, which highlight the impact of telomeres and telomerase targeted therapies in hematologic dysfunctions.
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48
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Hapangama DK, Kamal A, Saretzki G. Implications of telomeres and telomerase in endometrial pathology. Hum Reprod Update 2017; 23:166-187. [PMID: 27979878 PMCID: PMC5850744 DOI: 10.1093/humupd/dmw044] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 12/02/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Eukaryotic chromosomal ends are linear and are protected by nucleoprotein complexes known as telomeres. The complex structural anatomy and the diverse functions of telomeres as well as the unique reverse transcriptase enzyme, telomerase that maintains telomeres are under intensive scientific scrutiny. Both are involved in many human diseases including cancer, but also in ageing and chronic disease such as diabetes. Their intricate involvement in many cellular processes and pathways is being dynamically deciphered in many organs including the endometrium. This review summarizes our current knowledge on the topic of telomeres and telomerase and their potential role in providing plausible explanations for endometrial aberrations related to common gynaecological pathologies. OBJECTIVE AND RATIONALE This review outlines the recent major findings in telomere and telomerase functions in the context of endometrial biology. It highlights the contemporary discoveries in hormonal regulation, normal endometrial regeneration, stem cells and common gynaecological diseases such as endometriosis, infertility, recurrent reproductive failure and endometrial cancer (EC). SEARCH METHODS The authors carried out systematic PubMed (Medline) and Ovid searches using the key words: telomerase, telomeres, telomere length, human telomerase reverse transcriptase, telomeric RNA component, with endometrium, hormonal regulation, endometrial stem/progenitor cells, endometrial regeneration, endometriosis, recurrent miscarriage, infertility, endometrial hyperplasia, EC and uterine cancer. Publications used in this review date from 1995 until 31st June 2016. OUTCOMES The human endometrium is a unique somatic organ, which displays dynamic telomerase activity (TA) related to the menstrual cycle. Telomerase is implicated in almost all endometrial pathologies and appears to be crucial to endometrial stem cells. In particular, it is vital for normal endometrial regeneration, providing a distinct route to formulate possible curative, non-hormonal therapies to treat chronic endometrial conditions. Furthermore, our current understanding of telomere maintenance in EC is incomplete. Data derived from other malignancies on the role of telomerase in carcinogenesis cannot be extrapolated to EC because unlike in other cancers, TA is already present in proliferating healthy endometrial cells. WIDER IMPLICATIONS Since telomerase is pivotal to endometrial regeneration, further studies elucidating the role of telomeres, telomerase, their associated proteins and their regulation in normal endometrial regeneration as well as their role in endometrial pathologies are essential. This approach may allow future development of novel treatment strategies that are not only non-hormonal but also potentially curative.
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Affiliation(s)
- D K Hapangama
- Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, L8 7SS, UK.,Liverpool Women's Hospital NHS Foundation Trust, Crown Street, Liverpool L8 7SS, UK
| | - A Kamal
- Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, L8 7SS, UK.,The National Center for Early Detection of Cancer, Oncology Teaching Hospital, Baghdad Medical City, Baghdad, Iraq
| | - G Saretzki
- Institute for Ageing and Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK
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Non-coding RNAs and disease: the classical ncRNAs make a comeback. Biochem Soc Trans 2017; 44:1073-8. [PMID: 27528754 DOI: 10.1042/bst20160089] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Indexed: 01/16/2023]
Abstract
Many human diseases have been attributed to mutation in the protein coding regions of the human genome. The protein coding portion of the human genome, however, is very small compared with the non-coding portion of the genome. As such, there are a disproportionate number of diseases attributed to the coding compared with the non-coding portion of the genome. It is now clear that the non-coding portion of the genome produces many functional non-coding RNAs and these RNAs are slowly being linked to human diseases. Here we discuss examples where mutation in classical non-coding RNAs have been attributed to human disease and identify the future potential for the non-coding portion of the genome in disease biology.
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Wei D, Xie J, Yin B, Hao H, Song X, Liu Q, Zhang C, Sun Y. Significantly lengthened telomere in granulosa cells from women with polycystic ovarian syndrome (PCOS). J Assist Reprod Genet 2017; 34:861-866. [PMID: 28502062 DOI: 10.1007/s10815-017-0945-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 05/02/2017] [Indexed: 11/25/2022] Open
Abstract
PURPOSE Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women at reproductive age. However, its etiology remains poorly understood. Recent studies indicated that telomere length was related to PCOS. However, the association between telomere length and PCOS has only been shown in leucocytes and remained controversial across different studies. To clarify the association between telomere length and PCOS, the current study interrogated telomere length not only in leucocytes, but also in follicular granulosa cells, which is essential for folliculogenesis and steroidogenesis. METHODS Seventy-five patients with PCOS and 81 controls with mechanical infertility undergoing their first in vitro fertilization cycle were enrolled. Their peripheral blood and granulosa cells were collected on the oocyte retrieval day. Telomere length of both leucocytes in the blood and granulosa cells was assayed by quantitative polymerase chain reaction. RESULTS No significant difference was found in the leucocyte telomere length between controls and PCOS patients (0.99 ± 0.44 vs. 1.00 ± 0.38, p = 0.93). Interestingly, when comparing telomere length in granulosa cells between controls and PCOS subjects, significantly lengthened telomere length was found in PCOS subjects (1.00 ± 0.37 vs. 1.57±0.67, p < 0.0001). After adjustments for age and body mass index, the p value remained significant (p < 0.0001). CONCLUSIONS This finding reinforced the association between telomere abnormalities and PCOS. Given the importance of telomere length in cellular proliferation, our findings provided novel insights into the pathophysiology of PCOS that abnormalities in telomere length possibly disturb folliculogenesis and subsequently result in PCOS.
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Affiliation(s)
- Duo Wei
- The First Affiliated Hospital of Zhendzhou University, 1 Jianshedong Rd, Zhengzhou City, Henan, 450003, China
- Reproductive Medicine Center, the People's Hospital of Zhengzhou University, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China
- Reproductive Medicine Center, the People's Hospital of Henan Province, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China
| | - Juanke Xie
- Reproductive Medicine Center, the People's Hospital of Zhengzhou University, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China
- Reproductive Medicine Center, the People's Hospital of Henan Province, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China
| | - Baoli Yin
- Reproductive Medicine Center, the People's Hospital of Zhengzhou University, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China
- Reproductive Medicine Center, the People's Hospital of Henan Province, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China
| | - Haoying Hao
- Reproductive Medicine Center, the People's Hospital of Zhengzhou University, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China
- Reproductive Medicine Center, the People's Hospital of Henan Province, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China
| | - Xiaobing Song
- Reproductive Medicine Center, the People's Hospital of Zhengzhou University, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China
- Reproductive Medicine Center, the People's Hospital of Henan Province, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China
| | - Qi Liu
- Reproductive Medicine Center, the People's Hospital of Zhengzhou University, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China
- Reproductive Medicine Center, the People's Hospital of Henan Province, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China
| | - Cuilian Zhang
- Reproductive Medicine Center, the People's Hospital of Zhengzhou University, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China.
- Reproductive Medicine Center, the People's Hospital of Henan Province, 7 Weiwu Rd, Zhengzhou City, Henan, 450003, China.
| | - Yingpu Sun
- The First Affiliated Hospital of Zhendzhou University, 1 Jianshedong Rd, Zhengzhou City, Henan, 450003, China.
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