英国牛津大学Skirmantas Kriaucionis等研究人员合作发现，人类DNA聚合酶ε是CpG二核苷酸中C>T突变的来源。这一研究成果于2024年10月10日在线发表在国际学术期刊《自然—遗传学》上。

研究人员表示，CpG二核苷酸中的C-to-T转换是人类癌症和遗传疾病中最常见的突变类型。这些突变被归因于5-甲基胞嘧啶（5mC）的脱氨作用，这是一种出现在CpG上的表观遗传修饰。

研究人员最近将CpG>TpG突变与复制过程联系起来，并假设由DNA聚合酶ε（Pol ε）引入的错误可能是突变的另一种来源。

研究人员提出了一种称为聚合酶错误率测序（PER-seq）的新方法，用于单独测量DNA聚合酶的错误谱系。研究人员发现，最常见的人类癌症相关Pol ε突变体（P286R）会产生过多的CpG>TpG错误，模拟携带此突变的肿瘤以及错配修复缺陷的突变谱。

值得注意的是，研究人员还发现野生型Pol ε在复制5mCpG时的错误率比在其他背景中的C高出七倍。综合PER-seq和人类癌症的研究结果表明，复制错误是复制细胞中CpG>TpG突变的重要贡献者，这从根本上改变了人们对这一重要致病突变机制的理解。

附：英文原文

Title: Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides

Author: Tomkova, Marketa, McClellan, Michael John, Crevel, Gilles, Shahid, Akbar Muhammed, Mozumdar, Nandini, Tomek, Jakub, Shepherd, Emelie, Cotterill, Sue, Schuster-Bckler, Benjamin, Kriaucionis, Skirmantas

Issue&Volume: 2024-10-10

Abstract: C-to-T transitions in CpG dinucleotides are the most prevalent mutations in human cancers and genetic diseases. These mutations have been attributed to deamination of 5-methylcytosine (5mC), an epigenetic modification found on CpGs. We recently linked CpG>TpG mutations to replication and hypothesized that errors introduced by polymerase ε (Pol ε) may represent an alternative source of mutations. Here we present a new method called polymerase error rate sequencing (PER-seq) to measure the error spectrum of DNA polymerases in isolation. We find that the most common human cancer-associated Pol ε mutant (P286R) produces an excess of CpG>TpG errors, phenocopying the mutation spectrum of tumors carrying this mutation and deficiencies in mismatch repair. Notably, we also discover that wild-type Pol ε has a sevenfold higher error rate when replicating 5mCpG compared to C in other contexts. Together, our results from PER-seq and human cancers demonstrate that replication errors are a major contributor to CpG>TpG mutagenesis in replicating cells, fundamentally changing our understanding of this important disease-causing mutational mechanism.

DOI: 10.1038/s41588-024-01945-x

Source: https://www.nature.com/articles/s41588-024-01945-x