# Transcription-Coupled Repair Promotes the Retention of Mutations in Coding Regions During Replication Stress

## TL;DR

This study shows how a DNA repair process called transcription-coupled repair influences where mutations occur in cells under replication stress, affecting cancer development.

## Contribution

The study reveals a new link between transcription-coupled repair and mutation distribution in human cells during replication stress.

## Key findings

- ERCC6-proficient cells retain stress-induced mutations in coding regions of active genes.
- ERCC6-deficient cells accumulate mutations in intergenic regions and show a senescence response.
- TC-NER activity biases mutation retention in transcriptionally active loci during replication stress.

## Abstract

Replication stress (RS) is a primary driver of genomic instability in cancer, yet the contribution of transcription-coupled repair (TC-NER) to this process remains unclear. Here, we investigate how the TC-NER factor ERCC6 (CSB) shapes mutational landscapes under RS. We found that ERCC6 deficiency biases early damage signaling toward a 53BP1-mediated response, ultimately leading to senescence. Conversely, ERCC6-proficient cells prioritize survival and proliferative recovery but at the expense of distinct genomic alterations. Whole-exome sequencing reveals that ERCC6 proficiency is associated with the retention of stress-induced mutations specifically within coding regions of transcriptionally active loci, whereas ERCC6-deficient cells accumulate variants primarily in intergenic regions. These findings suggest that while ERCC6 safeguards transcriptional continuity during RS, its activity is associated with a biased retention of stress-induced mutations within coding regions in the surviving cell population. These findings reveal a previously unrecognized link between transcription-coupled repair and mutation distribution in human cells, linking TC-NER to context-dependent somatic evolution and tumor heterogeneity.