PT - JOURNAL ARTICLE AU - Ilias Georgakopoulos-Soares AU - Gene Koh AU - Josef Jiricny AU - Martin Hemberg AU - Serena Nik-Zainal TI - Transcription-coupled repair and mismatch repair contribute towards preserving genome integrity at mononucleotide repeat tracts AID - 10.1101/584342 DP - 2019 Jan 01 TA - bioRxiv PG - 584342 4099 - http://biorxiv.org/content/early/2019/03/21/584342.short 4100 - http://biorxiv.org/content/early/2019/03/21/584342.full AB - 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. We introduce a novel way 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 novel analytical approach reveals new insights into the contribution of DNA repair towards indel mutagenesis in human cells.