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1
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Deryusheva EI, Machulin AV, Surin AA, Kravchenko SV, Surin AK, Galzitskaya OV. RNA-Binding S1 Domain in Bacterial, Archaeal and Eukaryotic Proteins as One of the Evolutionary Markers of Symbiogenesis. Int J Mol Sci 2024; 25:13057. [PMID: 39684768 DOI: 10.3390/ijms252313057] [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: 10/04/2024] [Revised: 11/25/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
The RNA-binding S1 domain is a β-barrel with a highly conserved RNA-binding site on its surface. This domain is an important part of the structures of different bacterial, archaeal, and eukaryotic proteins. A distinctive feature of the S1 domain is multiple presences (structural repeats) in proteins and protein complexes. Here, we have analyzed all available protein sequences in the UniProt database to obtain data on the distribution of bacterial, eukaryotic and archaeal proteins containing the S1 domain. Mainly, the S1 domain is found in bacterial proteins with the number of domains varying from one to eight. Eukaryotic proteins contain from one to fifteen S1 domains, while in archaeal proteins, only one S1 domain is identified. Analysis of eukaryotic proteins containing S1 domains revealed a group of chloroplast S1 ribosomal proteins (ChRpS1) with characteristic properties of bacterial S1 ribosomal proteins (RpS1) from the Cyanobacteria. Also, in a separate group, chloroplast and mitochondrial elongation factor Ts containing two S1 structural domains were assigned. For mitochondrial elongation factor Ts, the features of S1 in comparison with the RpS1 from Cyanobacteria phylum and the Alphaproteobacteria class were revealed. The data obtained allow us to consider the S1 domain as one of the evolutionary markers of the symbiogenesis of bacterial and eukaryotic organisms.
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Affiliation(s)
- Evgenia I Deryusheva
- Institute for Biological Instrumentation, Federal Research Center "Pushchino Scientific Center for Biological Research of Russian Academy of Science", Russian Academy of Science, 142290 Pushchino, Russia
| | - Andrey V Machulin
- Skryabin Institute of Biochemistry and Physiology of Microorganisms, Federal Research Center "Pushchino Scientific Center for Biological Research of Russian Academy of Science", Russian Academy of Science, 142290 Pushchino, Russia
| | - Alexey A Surin
- Faculty of Informatics and Computer Engineering, MIREA-Russian Technological University, 119454 Moscow, Russia
| | - Sergey V Kravchenko
- Institute of Environmental and Agricultural Biology (X-BIO), Tyumen State University, 625003 Tyumen, Russia
| | - Alexey K Surin
- Institute of Environmental and Agricultural Biology (X-BIO), Tyumen State University, 625003 Tyumen, Russia
- Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Russia
- Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 142290 Pushchino, Russia
- State Research Center for Applied Microbiology and Biotechnology, 142279 Obolensk, Russia
| | - Oxana V Galzitskaya
- Institute of Environmental and Agricultural Biology (X-BIO), Tyumen State University, 625003 Tyumen, Russia
- Institute of Protein Research, Russian Academy of Sciences, 142290 Pushchino, Russia
- Institute for Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia
- Gamaleya Research Centre of Epidemiology and Microbiology, 123098 Moscow, Russia
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2
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Martin S, Katainen R, Taira A, Välimäki N, Ristimäki A, Seppälä T, Renkonen-Sinisalo L, Lepistö A, Tahkola K, Mattila A, Koskensalo S, Mecklin JP, Rajamäki K, Palin K, Aaltonen LA. Lynch syndrome-associated and sporadic microsatellite unstable colorectal cancers: different patterns of clonal evolution yield highly similar tumours. Hum Mol Genet 2024; 33:1858-1872. [PMID: 39180486 PMCID: PMC11540923 DOI: 10.1093/hmg/ddae124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/22/2024] [Accepted: 08/13/2024] [Indexed: 08/26/2024] Open
Abstract
Microsatellite unstable colorectal cancer (MSI-CRC) can arise through germline mutations in mismatch repair (MMR) genes in individuals with Lynch syndrome (LS), or sporadically through promoter methylation of the MMR gene MLH1. Despite the different origins of hereditary and sporadic MSI tumours, their genomic features have not been extensively compared. A prominent feature of MMR-deficient genomes is the occurrence of many indels in short repeat sequences, an understudied mutation type due to the technical challenges of variant calling in these regions. In this study, we performed whole genome sequencing and RNA-sequencing on 29 sporadic and 14 hereditary MSI-CRCs. We compared the tumour groups by analysing genome-wide mutation densities, microsatellite repeat indels, recurrent protein-coding variants, signatures of single base, doublet base, and indel mutations, and changes in gene expression. We show that the mutational landscapes of hereditary and sporadic MSI-CRCs, including mutational signatures and mutation densities genome-wide and in microsatellites, are highly similar. Only a low number of differentially expressed genes were found, enriched to interferon-γ regulated immune response pathways. Analysis of the variance in allelic fractions of somatic variants in each tumour group revealed higher clonal heterogeneity in sporadic MSI-CRCs. Our results suggest that the differing molecular origins of MMR deficiency in hereditary and sporadic MSI-CRCs do not result in substantial differences in the mutational landscapes of these tumours. The divergent patterns of clonal evolution between the tumour groups may have clinical implications, as high clonal heterogeneity has been associated with decreased tumour immunosurveillance and reduced responsiveness to immunotherapy.
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Affiliation(s)
- Samantha Martin
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Riku Katainen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Aurora Taira
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Niko Välimäki
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Ari Ristimäki
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Department of Pathology, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 3, 00290 Helsinki, Finland
| | - Toni Seppälä
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Haartmaninkatu 4, 00290 Helsinki, Finland
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and TAYS Cancer Centre, Kuntokatu 2, 33520 Tampere, Finland
- Faculty of Medicine and Health Technology, Tampere University, Kalevantie 4, 33100 Tampere, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Laura Renkonen-Sinisalo
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Haartmaninkatu 4, 00290 Helsinki, Finland
| | - Anna Lepistö
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Haartmaninkatu 4, 00290 Helsinki, Finland
| | - Kyösti Tahkola
- Faculty of Medicine and Health Technology, Tampere University, Kalevantie 4, 33100 Tampere, Finland
- Department of Surgery, Central Finland Health Care District, Keskussairaalantie 19, 40620 Jyväskylä, Finland
| | - Anne Mattila
- Department of Surgery, Central Finland Health Care District, Keskussairaalantie 19, 40620 Jyväskylä, Finland
| | - Selja Koskensalo
- The HUCH Gastrointestinal Clinic, Helsinki University Central Hospital, Stenbäckinkatu 9A, 00029 Helsinki, Finland
| | - Jukka-Pekka Mecklin
- Department of Education and Research, The Wellbeing Services of Central Finland, Hoitajatie 1, 40620 Jyväskylä, Finland
- Department of Sport and Health Sciences, University of Jyväskylä, Seminaarinkatu 15, 40014 Jyväskylä, Finland
| | - Kristiina Rajamäki
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Kimmo Palin
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
| | - Lauri A Aaltonen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland
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3
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Redelings BD, Holmes I, Lunter G, Pupko T, Anisimova M. Insertions and Deletions: Computational Methods, Evolutionary Dynamics, and Biological Applications. Mol Biol Evol 2024; 41:msae177. [PMID: 39172750 PMCID: PMC11385596 DOI: 10.1093/molbev/msae177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 07/02/2024] [Accepted: 07/09/2024] [Indexed: 08/24/2024] Open
Abstract
Insertions and deletions constitute the second most important source of natural genomic variation. Insertions and deletions make up to 25% of genomic variants in humans and are involved in complex evolutionary processes including genomic rearrangements, adaptation, and speciation. Recent advances in long-read sequencing technologies allow detailed inference of insertions and deletion variation in species and populations. Yet, despite their importance, evolutionary studies have traditionally ignored or mishandled insertions and deletions due to a lack of comprehensive methodologies and statistical models of insertions and deletion dynamics. Here, we discuss methods for describing insertions and deletion variation and modeling insertions and deletions over evolutionary time. We provide practical advice for tackling insertions and deletions in genomic sequences and illustrate our discussion with examples of insertions and deletion-induced effects in human and other natural populations and their contribution to evolutionary processes. We outline promising directions for future developments in statistical methodologies that would allow researchers to analyze insertions and deletion variation and their effects in large genomic data sets and to incorporate insertions and deletions in evolutionary inference.
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Affiliation(s)
| | - Ian Holmes
- Department of Bioengineering, University of California, Berkeley, CA 94720, USA
- Calico Life Sciences LLC, South San Francisco, CA 94080, USA
| | - Gerton Lunter
- Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Tal Pupko
- The Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Maria Anisimova
- Institute of Computational Life Sciences, Zurich University of Applied Sciences, Wädenswil, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
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4
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Choi JW, Lee JO, Lee S. Detecting microsatellite instability by length comparison of microsatellites in the 3' untranslated region with RNA-seq. Brief Bioinform 2024; 25:bbae423. [PMID: 39210504 PMCID: PMC11361843 DOI: 10.1093/bib/bbae423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/30/2024] [Accepted: 08/09/2024] [Indexed: 09/04/2024] Open
Abstract
Microsatellite instability (MSI), a phenomenon caused by deoxyribonucleic acid (DNA) mismatch repair system deficiencies, is an important biomarker in cancer research and clinical diagnostics. MSI detection often involves next-generation sequencing data, with many studies focusing on DNA. Here, we introduce a novel approach by measuring microsatellite lengths directly from ribonucleic acid sequencing (RNA-seq) data and comparing its distribution to detect MSI. Our findings reveal distinct instability patterns between MSI-high (MSI-H) and microsatellite stable samples, indicating the efficacy of RNA-based MSI detection. Additionally, microsatellites in the 3'-untranslated regions showed the greatest predictive value for MSI detection. Notably, this efficacy extends to detecting MSI-H samples even in tumors not commonly associated with MSI. Our approach highlights the utility of RNA-seq data in MSI detection, facilitating more precise diagnostics through the integration of various biological data.
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Affiliation(s)
- Jin-Wook Choi
- Department of Health Science and Technology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, 08826 Seoul, Republic of Korea
| | - Jin-Ok Lee
- Department of Health Science and Technology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, 08826 Seoul, Republic of Korea
| | - Sejoon Lee
- Department of Health Science and Technology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, 08826 Seoul, Republic of Korea
- Department of Pathology and Translational Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173beon-gil, Bundang-gu, 13620 Seongnam, Republic of Korea
- Precision Medicine Center, Seoul National University Bundang Hospital, 82 Gumi-ro, Bundang-gu, 13620 Seongnam, Republic of Korea
- Department of Genomic Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro, Bundang-gu, 13620 Seongnam, Republic of Korea
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5
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Verbiest MA, Lundström O, Xia F, Baudis M, Bilgin Sonay T, Anisimova M. Short tandem repeat mutations regulate gene expression in colorectal cancer. Sci Rep 2024; 14:3331. [PMID: 38336885 PMCID: PMC10858039 DOI: 10.1038/s41598-024-53739-0] [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: 12/15/2023] [Accepted: 02/04/2024] [Indexed: 02/12/2024] Open
Abstract
Short tandem repeat (STR) mutations are prevalent in colorectal cancer (CRC), especially in tumours with the microsatellite instability (MSI) phenotype. While STR length variations are known to regulate gene expression under physiological conditions, the functional impact of STR mutations in CRC remains unclear. Here, we integrate STR mutation data with clinical information and gene expression data to study the gene regulatory effects of STR mutations in CRC. We confirm that STR mutability in CRC highly depends on the MSI status, repeat unit size, and repeat length. Furthermore, we present a set of 1244 putative expression STRs (eSTRs) for which the STR length is associated with gene expression levels in CRC tumours. The length of 73 eSTRs is associated with expression levels of cancer-related genes, nine of which are CRC-specific genes. We show that linear models describing eSTR-gene expression relationships allow for predictions of gene expression changes in response to eSTR mutations. Moreover, we found an increased mutability of eSTRs in MSI tumours. Our evidence of gene regulatory roles for eSTRs in CRC highlights a mostly overlooked way through which tumours may modulate their phenotypes. Future extensions of these findings could uncover new STR-based targets in the treatment of cancer.
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Affiliation(s)
- Max A Verbiest
- Institute of Computational Life Sciences, Zurich University of Applied Sciences, Wädenswil, Switzerland.
- Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
- Swiss Institute of Bioinformatics, Lausanne, Switzerland.
| | - Oxana Lundström
- Institute of Computational Life Sciences, Zurich University of Applied Sciences, Wädenswil, Switzerland
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Feifei Xia
- Institute of Computational Life Sciences, Zurich University of Applied Sciences, Wädenswil, Switzerland
- Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Michael Baudis
- Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Tugce Bilgin Sonay
- Institute of Computational Life Sciences, Zurich University of Applied Sciences, Wädenswil, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
- Institute of Ecology, Evolution and Environmental Biology, Columbia University, New York, USA
| | - Maria Anisimova
- Institute of Computational Life Sciences, Zurich University of Applied Sciences, Wädenswil, Switzerland.
- Swiss Institute of Bioinformatics, Lausanne, Switzerland.
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6
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Deryusheva EI, Machulin AV, Galzitskaya OV. Diversity and features of proteins with structural repeats. Biophys Rev 2023; 15:1159-1169. [PMID: 37974986 PMCID: PMC10643770 DOI: 10.1007/s12551-023-01130-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 08/28/2023] [Indexed: 11/19/2023] Open
Abstract
The review provides information on proteins with structural repeats, including their classification, characteristics, functions, and relevance in disease development. It explores methods for identifying structural repeats and specialized databases. The review also highlights the potential use of repeat proteins as drug design scaffolds and discusses their evolutionary mechanisms.
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Affiliation(s)
- Evgeniya I. Deryusheva
- Institute for Biological Instrumentation, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Pushchino, Russia
| | - Andrey V. Machulin
- Skryabin Institute of Biochemistry and Physiology of Microorganisms, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Pushchino, Russia
| | - Oxana V. Galzitskaya
- Institute of Protein Research of the Russian Academy of Sciences, Pushchino, Russia
- Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences, Pushchino, Russia
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7
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Verbiest M, Maksimov M, Jin Y, Anisimova M, Gymrek M, Bilgin Sonay T. Mutation and selection processes regulating short tandem repeats give rise to genetic and phenotypic diversity across species. J Evol Biol 2023; 36:321-336. [PMID: 36289560 PMCID: PMC9990875 DOI: 10.1111/jeb.14106] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 06/29/2022] [Accepted: 08/01/2022] [Indexed: 02/03/2023]
Abstract
Short tandem repeats (STRs) are units of 1-6 bp that repeat in a tandem fashion in DNA. Along with single nucleotide polymorphisms and large structural variations, they are among the major genomic variants underlying genetic, and likely phenotypic, divergence. STRs experience mutation rates that are orders of magnitude higher than other well-studied genotypic variants. Frequent copy number changes result in a wide range of alleles, and provide unique opportunities for modulating complex phenotypes through variation in repeat length. While classical studies have identified key roles of individual STR loci, the advent of improved sequencing technology, high-quality genome assemblies for diverse species, and bioinformatics methods for genome-wide STR analysis now enable more systematic study of STR variation across wide evolutionary ranges. In this review, we explore mutation and selection processes that affect STR copy number evolution, and how these processes give rise to varying STR patterns both within and across species. Finally, we review recent examples of functional and adaptive changes linked to STRs.
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Affiliation(s)
- Max Verbiest
- Institute of Computational Life Sciences, School of Life Sciences and Facility ManagementZürich University of Applied SciencesWädenswilSwitzerland
- Department of Molecular Life SciencesUniversity of ZurichZurichSwitzerland
- Swiss Institute of BioinformaticsLausanneSwitzerland
| | - Mikhail Maksimov
- Department of Computer Science & EngineeringUniversity of California San DiegoLa JollaCaliforniaUSA
- Department of MedicineUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Ye Jin
- Department of MedicineUniversity of California San DiegoLa JollaCaliforniaUSA
- Department of BioengineeringUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Maria Anisimova
- Institute of Computational Life Sciences, School of Life Sciences and Facility ManagementZürich University of Applied SciencesWädenswilSwitzerland
- Swiss Institute of BioinformaticsLausanneSwitzerland
| | - Melissa Gymrek
- Department of Computer Science & EngineeringUniversity of California San DiegoLa JollaCaliforniaUSA
- Department of MedicineUniversity of California San DiegoLa JollaCaliforniaUSA
| | - Tugce Bilgin Sonay
- Institute of Ecology, Evolution and Environmental BiologyColumbia UniversityNew YorkNew YorkUSA
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Shukla S, Lazarchuk P, Pavlova MN, Sidorova JM. Genome-wide survey of D/E repeats in human proteins uncovers their instability and aids in identifying their role in the chromatin regulator ATAD2. iScience 2022; 25:105464. [PMCID: PMC9672403 DOI: 10.1016/j.isci.2022.105464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/03/2022] [Accepted: 10/26/2022] [Indexed: 11/15/2022] Open
Abstract
D/E repeats are stretches of aspartic and/or glutamic acid residues found in over 150 human proteins. We examined genomic stability of D/E repeats and functional characteristics of D/E repeat-containing proteins vis-à-vis the proteins with poly-Q or poly-A repeats, which are known to undergo pathologic expansions. Mining of tumor sequencing data revealed that D/E repeat-coding regions are similar to those coding poly-Qs and poly-As in increased incidence of trinucleotide insertions/deletions but differ in types and incidence of substitutions. D/E repeat-containing proteins preferentially function in chromatin metabolism and are the more likely to be nuclear and interact with core histones, the longer their repeats are. One of the longest D/E repeats of unknown function is in ATAD2, a bromodomain family ATPase frequently overexpressed in tumors. We demonstrate that D/E repeat deletion in ATAD2 suppresses its binding to nascent and mature chromatin and to the constitutive pericentromeric heterochromatin, where ATAD2 represses satellite transcription.
Many human proteins contain runs of aspartic/glutamic acid residues (D/E repeats) D/E repeats show increased incidence of in-frame insertions/deletions in tumors Nuclear and histone-interacting proteins often have long D/E repeats D/E repeat of the oncogene ATAD2 controls its binding to pericentric chromatin
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Affiliation(s)
- Shalabh Shukla
- Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific St., Box 357705, Seattle, WA 98195, USA
| | - Pavlo Lazarchuk
- Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific St., Box 357705, Seattle, WA 98195, USA
| | - Maria N. Pavlova
- Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific St., Box 357705, Seattle, WA 98195, USA
| | - Julia M. Sidorova
- Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific St., Box 357705, Seattle, WA 98195, USA
- Corresponding author
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9
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Moon C, Gordon M, Moon D, Reynolds T. Microsatellite Instability Analysis (MSA) for Bladder Cancer: Past History and Future Directions. Int J Mol Sci 2021; 22:ijms222312864. [PMID: 34884669 PMCID: PMC8657622 DOI: 10.3390/ijms222312864] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 11/11/2021] [Accepted: 11/19/2021] [Indexed: 12/18/2022] Open
Abstract
Microsatellite instability (MSI), the spontaneous loss or gain of nucleotides from repetitive DNA tracts, is a diagnostic phenotype for gastrointestinal, endometrial, colorectal, and bladder cancers; yet a landscape of instability events across a wider variety of cancer types is beginning to be discovered. The epigenetic inactivation of the MLH1 gene is often associated with sporadic MSI cancers. Recent next-generation sequencing (NGS)-based analyses have comprehensively characterized MSI-positive (MSI+) cancers, and several approaches to the detection of the MSI phenotype of tumors using NGS have been developed. Bladder cancer (here we refer to transitional carcinoma of the bladder) is a major cause of morbidity and mortality in the Western world. Cystoscopy, a gold standard for the detection of bladder cancer, is invasive and sometimes carries unwanted complications, while its cost is relatively high. Urine cytology is of limited value due to its low sensitivity, particularly to low-grade tumors. Therefore, over the last two decades, several new "molecular assays" for the diagnosis of urothelial cancer have been developed. Here, we provide an update on the development of a microsatellite instability assay (MSA) and the development of MSA associated with bladder cancers, focusing on findings obtained from urine analysis from bladder cancer patients as compared with individuals without bladder cancer. In our review, based on over 18 publications with approximately 900 sample cohorts, we provide the sensitivity (87% to 90%) and specificity (94% to 98%) of MSA. We also provide a comparative analysis between MSA and other assays, as well as discussing the details of four different FDA-approved assays. We conclude that MSA is a potentially powerful test for bladder cancer detection and may improve the quality of life of bladder cancer patients.
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Affiliation(s)
- Chulso Moon
- Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical Institution, Cancer Research Building II, 5M3, 1550 Orleans Street, Baltimore, MD 21205, USA
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA; (M.G.); (D.M.)
- BCD Innovations USA, 10606 Candlewick Road, Lutherville, MD 21093, USA
- Correspondence: ; Tel.: +1-(443)-370-5056
| | - Maxie Gordon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA; (M.G.); (D.M.)
- BCD Innovations USA, 10606 Candlewick Road, Lutherville, MD 21093, USA
| | - David Moon
- HJM Cancer Research Foundation Corporation, 10606 Candlewick Road, Lutherville, MD 21093, USA; (M.G.); (D.M.)
| | - Thomas Reynolds
- NEXT Bio-Research Services, LLC, 11601 Ironbridge Road, Suite 101, Chester, VA 23831, USA;
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10
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Deryusheva EI, Machulin AV, Galzitskaya OV. Structural, Functional, and Evolutionary Characteristics of Proteins with Repeats. Mol Biol 2021. [DOI: 10.1134/s0026893321040038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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11
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Jain S, Mazaheri B, Raviv N, Bruck J. Glioblastoma signature in the DNA of blood-derived cells. PLoS One 2021; 16:e0256831. [PMID: 34495981 PMCID: PMC8425531 DOI: 10.1371/journal.pone.0256831] [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: 04/26/2021] [Accepted: 08/16/2021] [Indexed: 11/19/2022] Open
Abstract
Current approach for the detection of cancer is based on identifying genetic mutations typical to tumor cells. This approach is effective only when cancer has already emerged, however, it might be in a stage too advanced for effective treatment. Cancer is caused by the continuous accumulation of mutations; is it possible to measure the time-dependent information of mutation accumulation and predict the emergence of cancer? We hypothesize that the mutation history derived from the tandem repeat regions in blood-derived DNA carries information about the accumulation of the cancer driver mutations in other tissues. To validate our hypothesis, we computed the mutation histories from the tandem repeat regions in blood-derived exomic DNA of 3874 TCGA patients with different cancer types and found a statistically significant signal with specificity ranging from 66% to 93% differentiating Glioblastoma patients from other cancer patients. Our approach and findings offer a new direction for future cancer prediction and early cancer detection based on information derived from blood-derived DNA.
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Affiliation(s)
- Siddharth Jain
- Department of Electrical Engineering, California Institute of Technology, Pasadena, CA, United States of America
| | - Bijan Mazaheri
- Department of Computing and Mathematical Sciences, California Institute of Technology, Pasadena, CA, United States of America
| | - Netanel Raviv
- Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO, United States of America
| | - Jehoshua Bruck
- Department of Electrical Engineering, California Institute of Technology, Pasadena, CA, United States of America
- * E-mail:
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Verbiest MA, Delucchi M, Bilgin Sonay T, Anisimova M. Beyond Microsatellite Instability: Intrinsic Disorder as a Potential Link Between Protein Short Tandem Repeats and Cancer. FRONTIERS IN BIOINFORMATICS 2021; 1:685844. [DOI: 10.3389/fbinf.2021.685844] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/21/2021] [Indexed: 12/28/2022] Open
Abstract
Short tandem repeats (STRs) are abundant in genomic sequences and are known for comparatively high mutation rates; STRs therefore are thought to be a potent source of genetic diversity. In protein-coding sequences STRs primarily encode disorder-promoting amino acids and are often located in intrinsically disordered regions (IDRs). STRs are frequently studied in the scope of microsatellite instability (MSI) in cancer, with little focus on the connection between protein STRs and IDRs. We believe, however, that this relationship should be explicitly included when ascertaining STR functionality in cancer. Here we explore this notion using all canonical human proteins from SwissProt, wherein we detected 3,699 STRs. Over 80% of these consisted completely of disorder promoting amino acids. 62.1% of amino acids in STR sequences were predicted to also be in an IDR, compared to 14.2% for non-repeat sequences. Over-representation analysis showed STR-containing proteins to be primarily located in the nucleus where they perform protein- and nucleotide-binding functions and regulate gene expression. They were also enriched in cancer-related signaling pathways. Furthermore, we found enrichments of STR-containing proteins among those correlated with patient survival for cancers derived from eight different anatomical sites. Intriguingly, several of these cancer types are not known to have a MSI-high (MSI-H) phenotype, suggesting that protein STRs play a role in cancer pathology in non MSI-H settings. Their intrinsic link with IDRs could therefore be an attractive topic of future research to further explore the role of STRs and IDRs in cancer. We speculate that our observations may be linked to the known dosage-sensitivity of disordered proteins, which could hint at a concentration-dependent gain-of-function mechanism in cancer for proteins containing STRs and IDRs.
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13
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Annear DJ, Vandeweyer G, Elinck E, Sanchis-Juan A, French CE, Raymond L, Kooy RF. Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease. Sci Rep 2021; 11:2515. [PMID: 33510257 PMCID: PMC7844047 DOI: 10.1038/s41598-021-82050-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 12/29/2020] [Indexed: 11/09/2022] Open
Abstract
Expanded CGG-repeats have been linked to neurodevelopmental and neurodegenerative disorders, including the fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). We hypothesized that as of yet uncharacterised CGG-repeat expansions within the genome contribute to human disease. To catalogue the CGG-repeats, 544 human whole genomes were analyzed. In total, 6101 unique CGG-repeats were detected of which more than 93% were highly variable in repeat length. Repeats with a median size of 12 repeat units or more were always polymorphic but shorter repeats were often polymorphic, suggesting a potential intergenerational instability of the CGG region even for repeats units with a median length of four or less. 410 of the CGG repeats were associated with known neurodevelopmental disease genes or with strong candidate genes. Based on their frequency and genomic location, CGG repeats may thus be a currently overlooked cause of human disease.
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Affiliation(s)
- Dale J Annear
- Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
| | - Geert Vandeweyer
- Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
| | - Ellen Elinck
- Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
| | - Alba Sanchis-Juan
- NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.,Department of Haematology, NHS Blood and Transplant Centre, University of Cambridge, Cambridge, CB2 0PT, UK
| | - Courtney E French
- Department of Paediatrics, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - Lucy Raymond
- NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.,Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK
| | - R Frank Kooy
- Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
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14
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A New Census of Protein Tandem Repeats and Their Relationship with Intrinsic Disorder. Genes (Basel) 2020; 11:genes11040407. [PMID: 32283633 PMCID: PMC7230257 DOI: 10.3390/genes11040407] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 03/29/2020] [Accepted: 04/01/2020] [Indexed: 12/31/2022] Open
Abstract
Protein tandem repeats (TRs) are often associated with immunity-related functions and diseases. Since that last census of protein TRs in 1999, the number of curated proteins increased more than seven-fold and new TR prediction methods were published. TRs appear to be enriched with intrinsic disorder and vice versa. The significance and the biological reasons for this association are unknown. Here, we characterize protein TRs across all kingdoms of life and their overlap with intrinsic disorder in unprecedented detail. Using state-of-the-art prediction methods, we estimate that 50.9% of proteins contain at least one TR, often located at the sequence flanks. Positive linear correlation between the proportion of TRs and the protein length was observed universally, with Eukaryotes in general having more TRs, but when the difference in length is taken into account the difference is quite small. TRs were enriched with disorder-promoting amino acids and were inside intrinsically disordered regions. Many such TRs were homorepeats. Our results support that TRs mostly originate by duplication and are involved in essential functions such as transcription processes, structural organization, electron transport and iron-binding. In viruses, TRs are found in proteins essential for virulence.
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15
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Polymorphisms in the Bovine Tumour Necrosis Factor Receptor Type Two Gene (TNF-RII) and Cell Subpopulations Naturally Infected with Bovine Leukaemia Virus. J Vet Res 2019; 63:175-182. [PMID: 31276056 PMCID: PMC6598189 DOI: 10.2478/jvetres-2019-0032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 04/12/2019] [Indexed: 11/20/2022] Open
Abstract
Introduction Numerous mutations in the bovine tumour necrosis factor receptor type two (TNF-RII) gene have been identified, but their biological consequences remain poorly understood. The aim of this study was to determine whether polymorphism in the analysed loci of the bovine TNF-RII gene is linked with the size of cell subpopulations naturally infected with bovine leukaemia virus (BLV) which serve important immune functions in the host. Material and Methods Samples originated from 78 cows. Polymorphisms in the studied gene were determined by PCR-RFLP and DNA sequencing by capillary electrophoresis. BLV infection was diagnosed by the immunofluorescence (IMF) technique and nested PCR. Cell subpopulations were immunophenotyped with IMF. Results Similar and non-significant differences in the average percentages of TNFα±, IgM+TNFα±, and CD11b+TNFα±cells infected with BLV were noted in individuals with various genotypes in the polymorphic sites g.-1646T > G and g. 16534T > C of the TNF-RII gene, and significant differences in the percentages of these subpopulations were observed between selected microsatellite genotypes (g.16512CA(n)). Conclusion STR polymorphism and the number of CA dinucleotide repeats in intron 1 of the TNF-RII gene influence the frequency of TNF+, CD11b+TNF+, and IgM+TNF+ subpopulations naturally infected with BLV. Polymorphism in the gene's other two sites do not affect the size of these cell subpopulations.
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16
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Farnoud F, Schwartz M, Bruck J. Estimation of duplication history under a stochastic model for tandem repeats. BMC Bioinformatics 2019; 20:64. [PMID: 30727948 PMCID: PMC6364452 DOI: 10.1186/s12859-019-2603-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 01/03/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Tandem repeat sequences are common in the genomes of many organisms and are known to cause important phenomena such as gene silencing and rapid morphological changes. Due to the presence of multiple copies of the same pattern in tandem repeats and their high variability, they contain a wealth of information about the mutations that have led to their formation. The ability to extract this information can enhance our understanding of evolutionary mechanisms. RESULTS We present a stochastic model for the formation of tandem repeats via tandem duplication and substitution mutations. Based on the analysis of this model, we develop a method for estimating the relative mutation rates of duplications and substitutions, as well as the total number of mutations, in the history of a tandem repeat sequence. We validate our estimation method via Monte Carlo simulation and show that it outperforms the state-of-the-art algorithm for discovering the duplication history. We also apply our method to tandem repeat sequences in the human genome, where it demonstrates the different behaviors of micro- and mini-satellites and can be used to compare mutation rates across chromosomes. It is observed that chromosomes that exhibit the highest mutation activity in tandem repeat regions are the same as those thought to have the highest overall mutation rates. However, unlike previous works that rely on comparing human and chimpanzee genomes to measure mutation rates, the proposed method allows us to find chromosomes with the highest mutation activity based on a single genome, in essence by comparing (approximate) copies of the pattern in tandem repeats. CONCLUSION The prevalence of tandem repeats in most organisms and the efficiency of the proposed method enable studying various aspects of the formation of tandem repeats and the surrounding sequences in a wide range of settings. AVAILABILITY The implementation of the estimation method is available at http://ips.lab.virginia.edu/smtr .
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Affiliation(s)
- Farzad Farnoud
- Department of Electrical and Computer Engineering, Department of Computer Science, University of Virginia, Charlottesville, USA
| | - Moshe Schwartz
- Department of Electrical and Computer Engineering, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Jehoshua Bruck
- Department of Electrical Engineering, California Institute of Technology, Pasadena, USA
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17
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Li S, Hu Z, Zhao Y, Huang S, He X. Transcriptome-Wide Analysis Reveals the Landscape of Aberrant Alternative Splicing Events in Liver Cancer. Hepatology 2019; 69:359-375. [PMID: 30014619 DOI: 10.1002/hep.30158] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 06/30/2018] [Indexed: 01/02/2023]
Abstract
Alternative splicing (AS) is assumed to be a pivotal determinant for the generation of diverse transcriptional variants in cancer. However, the comprehensive dysregulation of AS and the prospective biological and clinical relevance in hepatocellular carcinoma (HCC) remain obscure. Here, we identified and depicted the AS landscape in HCC by performing reference-based assembly of sequencing reads from over 600 RNA sequencing (RNA-seq) libraries. We detected various differentially spliced ASEs across patients covering not only protein-coding genes, but also considerable numbers of noncoding genes. Strikingly, alternative transcription initiation was found to frequently occur in HCC. These differential ASEs were highly related to "cancer hallmarks" and involved in metabolism-related pathways in particular. In addition, 243 differential ASEs were identified as risk predictors for HCC patient survival. The isoform switch of metabolism-related gene UGP2 (UDP-glucose pyrophosphorylase 2) might play an essential role in HCC. We further constructed regulatory networks between RNA-binding protein (RBP) genes and the corresponding ASEs. Further analysis demonstrated that the regulated networks were enriched in a variety of metabolism-related pathways. Conclusion: Differential ASEs are prevalent in HCC, where alternative transcription initiation was found to frequently occur. We found that genes having differential ASEs were significantly enriched in metabolism-related pathways. The expression variations, binding relations, and even mutations of RBP genes largely influenced differential ASEs in HCC.
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Affiliation(s)
- Shengli Li
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhixiang Hu
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yingjun Zhao
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shenglin Huang
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xianghuo He
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.,Collaborative Innovation Center for Cancer Medicine, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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18
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Lu R, Wang Y, Xu X, Xie S, Wang Y, Zhong A, Zheng H, Yu Y, Gao X, Guo L. Establishment of a detection assay for DNA endonuclease activity and its application in the screening and prognosis of malignant lymphoma. BMC BIOCHEMISTRY 2018; 19:6. [PMID: 30064372 PMCID: PMC6069817 DOI: 10.1186/s12858-018-0096-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 07/20/2018] [Indexed: 11/29/2022]
Abstract
BACKGROUND Endonucleases play critical roles in maintaining genomic stability and regulating cell growth. The purpose of this study was to evaluate detection of endonuclease activity as an indicator in the early diagnosis and prognosis of lymphoma. RESULTS The method of endonuclease activity determination was successfully established and applied to compare cancer patient and control cohorts. Endonuclease activities of cancer tissues were significantly higher than those of adjacent control tissues (P < 0.001). We next investigated endonuclease activity in peripheral blood of enrolled patients and the controls, which were also significantly higher in patients than in controls (P = 0.015). Additionally, endonuclease activities were elevated in the metastasis subgroup compared with the non-metastasis subgroup(P = 0.038), whereas no significant difference was found between age(≤ 56y, > 56y) and gender (P = 0.736 > 0.05 and P = 0.635 > 0.05, respectively). Although there was no significant difference between control group with the non-metastatic cancer patients (P = 0.800 > 0.05), endonuclease activities were lower in the control group compared with the non-metastatic cancer patients with lymphoma (P = 0.033). The progression-free survival probability of patients with elevated R ratios(R ratio ≥ 1.4) was significantly lower than that of patients with lower R ratios (R ratio < 1.4). CONCLUSIONS An assay was established to detect the endonuclease activity,which might be useful for the prognosis of cancers, especially lymphoma.
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Affiliation(s)
- Renquan Lu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, 270 DongAn Road, Xuhui District, Shanghai, 200032 China
| | - Yingchao Wang
- Department of Clinical Laboratory, Shanghai Proton and Heavy Ion Center, Shanghai, 201321 China
| | - Xiaofeng Xu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, 270 DongAn Road, Xuhui District, Shanghai, 200032 China
- Department of Clinical Laboratory, Shanghai Proton and Heavy Ion Center, Shanghai, 201321 China
| | - Suhong Xie
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, 270 DongAn Road, Xuhui District, Shanghai, 200032 China
| | - Yanchun Wang
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, 270 DongAn Road, Xuhui District, Shanghai, 200032 China
| | - Ailing Zhong
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, 270 DongAn Road, Xuhui District, Shanghai, 200032 China
| | - Hui Zheng
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, 270 DongAn Road, Xuhui District, Shanghai, 200032 China
| | - Yiwen Yu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, 270 DongAn Road, Xuhui District, Shanghai, 200032 China
| | - Xiang Gao
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, 270 DongAn Road, Xuhui District, Shanghai, 200032 China
| | - Lin Guo
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, 270 DongAn Road, Xuhui District, Shanghai, 200032 China
- Department of Clinical Laboratory, Shanghai Proton and Heavy Ion Center, Shanghai, 201321 China
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19
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Bagshaw AT. Functional Mechanisms of Microsatellite DNA in Eukaryotic Genomes. Genome Biol Evol 2017; 9:2428-2443. [PMID: 28957459 PMCID: PMC5622345 DOI: 10.1093/gbe/evx164] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2017] [Indexed: 02/06/2023] Open
Abstract
Microsatellite repeat DNA is best known for its length mutability, which is implicated in several neurological diseases and cancers, and often exploited as a genetic marker. Less well-known is the body of work exploring the widespread and surprisingly diverse functional roles of microsatellites. Recently, emerging evidence includes the finding that normal microsatellite polymorphism contributes substantially to the heritability of human gene expression on a genome-wide scale, calling attention to the task of elucidating the mechanisms involved. At present, these are underexplored, but several themes have emerged. I review evidence demonstrating roles for microsatellites in modulation of transcription factor binding, spacing between promoter elements, enhancers, cytosine methylation, alternative splicing, mRNA stability, selection of transcription start and termination sites, unusual structural conformations, nucleosome positioning and modification, higher order chromatin structure, noncoding RNA, and meiotic recombination hot spots.
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20
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Eifert C, Pantazi A, Sun R, Xu J, Cingolani P, Heyer J, Russell M, Lvova M, Ring J, Tse JY, Lyle S, Protopopov A. Clinical application of a cancer genomic profiling assay to guide precision medicine decisions. Per Med 2017; 14:309-325. [PMID: 28890729 PMCID: PMC5580078 DOI: 10.2217/pme-2017-0011] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 05/09/2017] [Indexed: 12/17/2022]
Abstract
Aim: Develop and apply a comprehensive and accurate next-generation sequencing based assay to help clinicians to match oncology patients to therapies. Materials & methods: The performance of the CANCERPLEX® assay was assessed using DNA from well-characterized routine clinical formalin-fixed paraffin-embedded (FFPE) specimens and cell lines. Results: The maximum sensitivity of the assay is 99.5% and its accuracy is virtually 100% for detecting somatic alterations with an allele fraction of as low as 10%. Clinically actionable variants were identified in 93% of patients (930 of 1000) who underwent testing. Conclusion: The test's capacity to determine all of the critical genetic changes, tumor mutation burden, microsatellite instability status and viral associations has important ramifications on clinical decision support strategies, including identification of patients who are likely to benefit from immune checkpoint blockage therapies.
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Affiliation(s)
- Cheryl Eifert
- KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA
| | - Angeliki Pantazi
- KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA
| | - Ruobai Sun
- KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA
| | - Jia Xu
- KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,IBM Watson Health, 75 Binney St., Cambridge, MA 02142, USA.,KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,IBM Watson Health, 75 Binney St., Cambridge, MA 02142, USA
| | - Pablo Cingolani
- KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA
| | - Joerg Heyer
- KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA
| | - Meaghan Russell
- KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA
| | - Maria Lvova
- KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA
| | - Jennifer Ring
- KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA
| | - Julie Y Tse
- KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,Department of Pathology, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St., Boston, MA 02111, USA.,KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,Department of Pathology, Tufts Medical Center, Tufts University School of Medicine, 800 Washington St., Boston, MA 02111, USA
| | - Stephen Lyle
- KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605, USA.,KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605, USA
| | - Alexei Protopopov
- KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA.,KEW, Inc., 840 Memorial Dr., Cambridge, MA 02139, USA
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21
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Classification and characterization of microsatellite instability across 18 cancer types. Nat Med 2016; 22:1342-1350. [PMID: 27694933 DOI: 10.1038/nm.4191] [Citation(s) in RCA: 687] [Impact Index Per Article: 76.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 08/29/2016] [Indexed: 12/16/2022]
Abstract
Microsatellite instability (MSI), the spontaneous loss or gain of nucleotides from repetitive DNA tracts, is a diagnostic phenotype for gastrointestinal, endometrial, and colorectal tumors, yet the landscape of instability events across a wider variety of cancer types remains poorly understood. To explore MSI across malignancies, we examined 5,930 cancer exomes from 18 cancer types at more than 200,000 microsatellite loci and constructed a genomic classifier for MSI. We identified MSI-positive tumors in 14 of the 18 cancer types. We also identified loci that were more likely to be unstable in particular cancer types, resulting in specific instability signatures that involved cancer-associated genes, suggesting that instability patterns reflect selective pressures and can potentially identify novel cancer drivers. We also observed a correlation between survival outcomes and the overall burden of unstable microsatellites, suggesting that MSI may be a continuous, rather than discrete, phenotype that is informative across cancer types. These analyses offer insight into conserved and cancer-specific properties of MSI and reveal opportunities for improved methods of clinical MSI diagnosis and cancer gene discovery.
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22
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Atkins JF, Loughran G, Bhatt PR, Firth AE, Baranov PV. Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use. Nucleic Acids Res 2016; 44:7007-78. [PMID: 27436286 PMCID: PMC5009743 DOI: 10.1093/nar/gkw530] [Citation(s) in RCA: 176] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 05/26/2016] [Indexed: 12/15/2022] Open
Abstract
Genetic decoding is not ‘frozen’ as was earlier thought, but dynamic. One facet of this is frameshifting that often results in synthesis of a C-terminal region encoded by a new frame. Ribosomal frameshifting is utilized for the synthesis of additional products, for regulatory purposes and for translational ‘correction’ of problem or ‘savior’ indels. Utilization for synthesis of additional products occurs prominently in the decoding of mobile chromosomal element and viral genomes. One class of regulatory frameshifting of stable chromosomal genes governs cellular polyamine levels from yeasts to humans. In many cases of productively utilized frameshifting, the proportion of ribosomes that frameshift at a shift-prone site is enhanced by specific nascent peptide or mRNA context features. Such mRNA signals, which can be 5′ or 3′ of the shift site or both, can act by pairing with ribosomal RNA or as stem loops or pseudoknots even with one component being 4 kb 3′ from the shift site. Transcriptional realignment at slippage-prone sequences also generates productively utilized products encoded trans-frame with respect to the genomic sequence. This too can be enhanced by nucleic acid structure. Together with dynamic codon redefinition, frameshifting is one of the forms of recoding that enriches gene expression.
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Affiliation(s)
- John F Atkins
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland School of Microbiology, University College Cork, Cork, Ireland Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Gary Loughran
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | - Pramod R Bhatt
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | - Andrew E Firth
- Division of Virology, Department of Pathology, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK
| | - Pavel V Baranov
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
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23
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Pai TW, Chen CM. SSRs as genetic markers in the human genome and their observable relationship to hereditary diseases. Biomark Med 2016; 10:563-6. [PMID: 27232109 DOI: 10.2217/bmm-2016-0094] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Tun-Wen Pai
- Department of Computer Science & Engineering, National Taiwan Ocean University, No. 2, Pei-Ning Road, Keelung 20224, Taiwan, R.O.C
| | - Chien-Ming Chen
- Department of Computer Science & Engineering, National Taiwan Ocean University, No. 2, Pei-Ning Road, Keelung 20224, Taiwan, R.O.C
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