Transcription-coupled repair and mismatch repair contribute towards preserving genome integrity at mononucleotide repeat tracts

Ilias Georgakopoulos-Soares, Gene Koh, Sophie E. Momen, Josef Jiricny, Martin Hemberg () and Serena Nik-Zainal ()
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Ilias Georgakopoulos-Soares: Wellcome Sanger Institute, Wellcome Genome Campus
Gene Koh: Wellcome Sanger Institute, Wellcome Genome Campus
Sophie E. Momen: University of Cambridge
Josef Jiricny: Institute of Molecular Life Sciences, University of Zurich and Institute of Biochemistry, ETH Zurich
Martin Hemberg: Wellcome Sanger Institute, Wellcome Genome Campus
Serena Nik-Zainal: University of Cambridge

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15901-w

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