1. Transcription-coupled repair and mismatch repair contribute towards preserving genome integrity at mononucleotide repeat tracts
- Author
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Sophie Momen, Martin Hemberg, Ilias Georgakopoulos-Soares, Josef Jiricny, Gene Koh, Serena Nik-Zainal, Koh, Gene [0000-0002-3840-4954], Hemberg, Martin [0000-0001-8895-5239], Nik-Zainal, Serena [0000-0001-5054-1727], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,DNA Repair ,Transcription, Genetic ,Amino Acid Motifs ,DNA Mutational Analysis ,General Physics and Astronomy ,Genome ,chemistry.chemical_compound ,0302 clinical medicine ,INDEL Mutation ,Transcription (biology) ,Neoplasms ,Cancer genomics ,DNA Breaks, Double-Stranded ,lcsh:Science ,Cancer ,Multidisciplinary ,article ,food and beverages ,Genomics ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,DNA mismatch repair ,DNA Replication ,631/67 ,DNA repair ,Science ,Polynucleotides ,Computational biology ,631/67/69 ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Humans ,Repetitive Sequences, Nucleic Acid ,45 ,Genome, Human ,Sequence Analysis, RNA ,Computational Biology ,Genetic Variation ,General Chemistry ,Computational biology and bioinformatics ,030104 developmental biology ,chemistry ,Mutagenesis ,Human genome ,lcsh:Q ,631/114 ,119 ,DNA ,Gene Deletion ,Nucleotide excision repair - Abstract
The mechanisms that underpin how insertions or deletions (indels) become fixed in DNA have primarily been ascribed to replication-related and/or double-strand break (DSB)-related processes. Here, we introduce a method to evaluate indels, orientating them relative to gene transcription. In so doing, we reveal a number of surprising findings: First, there is a transcriptional strand asymmetry in the distribution of mononucleotide repeat tracts in the reference human genome. Second, there is a strong transcriptional strand asymmetry of indels across 2,575 whole genome sequenced human cancers. We suggest that this is due to the activity of transcription-coupled nucleotide excision repair (TC-NER). Furthermore, TC-NER interacts with mismatch repair (MMR) under physiological conditions to produce strand bias. Finally, we show how insertions and deletions differ in their dependencies on these repair pathways. Our analytical approach reveals insights into the contribution of DNA repair towards indel mutagenesis in human cells., Nature Communications, 11 (1), ISSN:2041-1723
- Published
- 2020
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