Transcription-Coupled Repair Promotes the Retention of Mutations in Coding Regions 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. The

SUBMITTER: Zambrano E 

PROVIDER: S-EPMC12896993 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature