DNA polymerase α- primase can function as a translesion DNA polymerase

• 成果类型: Article
• 署名作者: Mayle, Ryan; Georgescu, Roxana; O'Donnell, Michael E.
• 署名单位: Howard Hughes Medical Institute; Rockefeller University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11923
• DOI: 10.1073/pnas.2517556122
• 发表日期: 2025-09-16
• 关键词: thymine-thymine dimer; saccharomyces-cerevisiae; replication; bypass; repair; 8-oxoguanine; FIDELITY; roles

摘要

Replication of cellular chromosomes requires a primase to generate short RNA primers to initiate genomic replication. While bacterial and archaeal primase generate short RNA primers, the eukaryotic primase, Polc-primase, contains both RNA primase and DNA polymerase (Pol) subunits that function together to form a >20 base hybrid RNA-DNA primer. Interestingly, the DNA Pol1 subunit of Polc lacks a 3'- 5' proofreading exonuclease, contrary to the high-fidelity normally associated with DNA replication. However, Polo and Pol epsilon synthesize the majority of the eukaryotic genome, and both contain 3'- 5' exonuclease activity for high fidelity. Nonetheless, even the small amount of DNA produced by Pol1 in each of the many RNA/DNA primers during chromosome replication adds up to tens of millions of nucleotides in a human genome. Thus, it has been a longstanding question why Pol1 lacks a proofreading exonuclease. We show here that Polc is uniquely capable of traversing common oxidized or hydrolyzed template nucleotides and propose that Polc evolved to bypass these common template lesions when they are encountered during chromosome replication. Additionally, we show a unique ability of replication factor C (RFC) to stimulate Polo lesion bypass, independent of its sliding clamp. This suggests that there may be a coordination between Polo and RFC that does not involve RFC loading of PCNA.