Sewell Allysa, Wyrick John J
School of Molecular Biosciences, Biotechnology Life Sciences, Washington State University, Pullman, WA, USA.
Nucleus. 2025 Dec;16(1):2476935. doi: 10.1080/19491034.2025.2476935. Epub 2025 Mar 13.
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 . 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.
S期的复制时间影响酵母和人类癌症中的突变率；然而，其中的确切机制仍不清楚。在这里，我们分析了复制时间对紫外线诱变的影响。我们的分析表明，野生型细胞中紫外线诱导的突变在基因组的早期复制区域富集，但在全球基因组核苷酸切除修复（GG-NER）缺陷的细胞中，突变在晚期复制区域富集。对紫外线损伤图谱的分析表明，环丁烷嘧啶二聚体在晚期复制区域富集，但这种富集几乎完全归因于重复的核糖体DNA。在GG-NER缺陷细胞的晚期复制区域，通常与跨损伤合成（TLS）活性相关的复杂突变也有所增加。我们提出，在具有修复能力的细胞中，早期复制区域的紫外线诱变率更高，因为在进行复制之前修复损伤的时间较少。然而，在没有GG-NER的情况下，增加的TLS活性会促进晚期复制区域的紫外线诱变。
