Replication stress (RS) is a primary driver of genomic instability in cancer, yet the contribution of transcription-coupled repair to this process remains poorly understood. Here, we investigate how the TC-NER factor ERCC6 (CSB) shapes mutational landscapes under RS. We demonstrate that ERCC6 deficiency impairs replication restart and 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 cost of distinct genomic alterations. Whole-exome sequencing reveals that ERCC6 drives 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 uncover a survival-mutagenesis trade-off: ERCC6 safeguards transcriptional continuity during replication stress but promotes mutational burdens in functional genomes. This mechanism parallels bacterial adaptive mutagenesis, identifying ERCC6 as a context-dependent driver of somatic evolution and tumor heterogeneity.