Affiliation:
1. Department of Chemistry, University of California Riverside, Riverside, CA 92521-0403
2. Environmental Toxicology Graduate Program, University of California Riverside, Riverside, CA 92521-0403
Abstract
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
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-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
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-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.
Funder
HHS | National Institutes of Health
Publisher
Proceedings of the National Academy of Sciences