Interplay of replication timing, DNA repair, and translesion synthesis in UV mutagenesis in yeast

Replication timing during S-phase impacts mutation rates in yeast and human cancers; however, the exact mechanism involved remains unclear. Here, we analyze the impact of replication timing on UV mutagenesis in <i>Saccharomyces cerevisiae</i>. Our analysis indicates that UV mutations are enriched in early-replicating regions of the genome in wild-type cells, but in cells deficient in global genomic-nucleotide excision repair (GG-NER), mutations are enriched in late-replicating regions. Analysis of UV damage maps revealed that cyclobutane pyrimidine dimers are enriched in late-replicating regions, but this enrichment is almost entirely due to repetitive ribosomal DNA. Complex mutations typically associated with TLS activity are also elevated in late-replicating regions in GG-NER deficient cells. We propose that UV mutagenesis is higher in early-replicating regions in repair-competent cells because there is less time to repair the lesion prior to undergoing replication. However, in the absence of GG-NER, increased TLS activity promotes UV mutagenesis in late-replicating regions.