Transcription-coupled repair and mismatch repair contribute towards preserving genome integrity at mononucleotide repeat tracts.
Momen, Sophie E
Nik-Zainal Abidin, Serena
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Georgakopoulos-Soares, I., Koh, G., Momen, S. E., Jiricny, J., Hemberg, M., & Nik-Zainal Abidin, S. (2020). Transcription-coupled repair and mismatch repair contribute towards preserving genome integrity at mononucleotide repeat tracts.. Nature communications, 11 (1), 1980. https://doi.org/10.1038/s41467-020-15901-w
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.
Humans, Neoplasms, Polynucleotides, DNA Mutational Analysis, Sequence Analysis, RNA, Computational Biology, Genomics, DNA Repair, DNA Replication, Transcription, Genetic, Gene Expression Regulation, Neoplastic, Mutagenesis, Gene Deletion, Amino Acid Motifs, Repetitive Sequences, Nucleic Acid, Genome, Human, DNA Breaks, Double-Stranded, INDEL Mutation, Genetic Variation
Cancer Research UK (CRUK) - C60100/A23916 [Nik-Zainal] Cancer Research UK (CRUK) - C60100/A25274 [Nik-Zainal]
Cancer Research UK (23916)
Cancer Research UK (25274)
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External DOI: https://doi.org/10.1038/s41467-020-15901-w
This record's URL: https://www.repository.cam.ac.uk/handle/1810/303956
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