DNA polymerase κ participates in early S-phase DNA replication in human cells

作者：Feng Tang, Yinan Wang, Ting Zhao, Jun Yuan, Andrew H. Kellum, Yinsheng Wang · 发表于：Proceedings of the National Academy of Sciences · 年份：2024 · DOI：10.1073/pnas.2405473121 · 被引用次数：7 · 研究领域：DNA Repair Mechanisms、Cancer-related Molecular Pathways、Cancer Genomics and Diagnostics

Cycling cells replicate their DNA during the S phase through a defined temporal program known as replication timing. Mutation frequencies, epigenetic chromatin states, and transcriptional activities are different for genomic regions that are replicated early and late in the S phase. Here, we found from ChIP-Seq analysis that DNA polymerase (Pol) κ is enriched in early-replicating genomic regions in HEK293T cells. In addition, by feeding cells with N 2 -heptynyl-2′-deoxyguanosine followed by click chemistry–based enrichment and high-throughput sequencing, we observed elevated Pol κ activities in genomic regions that are replicated early in the S phase. On the basis of the established functions of Pol κ in accurate and efficient nucleotide insertion opposite endogenously induced N 2 -modified dG lesions, our work suggests that active engagement of Pol κ may contribute to diminished mutation rates observed in early-replicating regions of the human genome, including cancer genomes. Together, our work expands the functions of Pol κ and offered a plausible mechanism underlying replication timing–dependent mutation accrual in the human genome.