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

Ilias Georgakopoulos-Soares,Sophie E Momen,Gene Koh,Josef Jiricny,Serena Nik-Zainal,Martin Hemberg

doi:10.1038/s41467-020-15901-w

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.

Highlights

The mechanisms that underpin how insertions or deletions become fixed in DNA have primarily been ascribed to replication-related and/or double-strand break (DSB)-related processes
Because these small insertion/deletion loops (IDLs) are efficiently repaired by mismatch repair (MMR), the density of deletions in microsatellites is higher in cells lacking MMR
The likelihood of formation of such loops increases with the length of the repeat and we confirm this by showing that indel frequency is augmented with increasing lengths of polynucleotide repeat tracts (Supplementary Fig. 1d, e) and is more pronounced in MMRdeficient samples

Summary

Introduction

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. 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). Transcription has been implicated in contributing to mutational strand asymmetries reflecting biases in DNA damage (transcription-associated damage) and DNA repair mechanisms (transcription-coupled repair) between the two strands[3,4,5] In this area, while substitutions in human cancers have been extensively studied, insertions/deletions (indels) have remained comparatively under-explored. We observe transcriptional strand asymmetry in insertions and deletions at mononucleotide repeat tracts across cancer types, and are able to attribute the relative contributions of transcription-coupled nucleotide excision repair (TC-NER) and mismatch repair (MMR) pathways to indel patterns in human somatic cells

Methods

Results

Conclusion