Zambrano, EvelynFierro, CristopherMorales, FernandaManterola, MarciaMarin, ArnaldoArmisen, RicardoMarcelain, Katherine2026-02-242026-02-242026Zambrano E, Fierro C, Morales F, et al. Transcription-Coupled Repair Promotes the Retention of Mutations in Coding Regions During Replication Stress. Int J Mol Sci. 2026;27(3):1154. Published 2026 Jan 23. doi:10.3390/ijms27031154https://hdl.handle.net/11447/10580Replication 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.enERCC6 (CSB)Genomic instabilityMutagenesisReplication stressTranscription-coupled nucleotide excision repair (TC-NER)Articlehttps://doi.org/10.3390/ijms27031154