a Relative number of mutations that occurred before and after SCNAs in XP-C cancer genomes (normalized per haploid DNA copy number). The majority of events demonstrate an excess of mutations that were accumulated before the SCNA and may have occurred in tumor-progenitor cells or at early stages of carcinogenesis. b A model of DNA lesion accumulation and mutagenesis in XP-C cells. In XP-C cells where GG-NER is dysfunctional, bulky lesions cannot be efficiently repaired and persist everywhere in the genome except transcribed strands of active genes where TC-NER is operative. During the S-phase a part of bulky lesions on the leading strand may be removed by error-free template switching (TS) mechanisms while on the lagging strand they are converted to mutations by error-prone translesion synthesis (TLS) more frequently, causing mutation accumulation with cell divisions and observed transcriptional and replication biases.