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

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dc.contributor.authorZambrano, Evelyn
dc.contributor.authorFierro, Cristopher
dc.contributor.authorMorales, Fernanda
dc.contributor.authorManterola, Marcia
dc.contributor.authorMarin, Arnaldo
dc.contributor.authorArmisen, Ricardo
dc.contributor.authorMarcelain, Katherine
dc.date.accessioned2026-02-24T21:10:01Z
dc.date.available2026-02-24T21:10:01Z
dc.date.issued2026
dc.description.abstractReplication 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.
dc.description.versionVersión Publicada
dc.identifier.citationZambrano 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/ijms27031154
dc.identifier.doihttps://doi.org/10.3390/ijms27031154
dc.identifier.urihttps://hdl.handle.net/11447/10580
dc.language.isoen
dc.subjectERCC6 (CSB)
dc.subjectGenomic instability
dc.subjectMutagenesis
dc.subjectReplication stress
dc.subjectTranscription-coupled nucleotide excision repair (TC-NER)
dc.titleTranscription-Coupled Repair Promotes the Retention of Mutations in Coding Regions During Replication Stress
dc.typeArticle
dcterms.accessRightsAcceso Abierto
dcterms.sourceInternational journal of molecular sciences
dspace.entity.typePublication
relation.isAuthorOfPublicationf814e5ac-2623-4a1f-bc2b-5a1a260ee316
relation.isAuthorOfPublication.latestForDiscoveryf814e5ac-2623-4a1f-bc2b-5a1a260ee316

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