DNA replication is complex and highly regulated, and DNA replication errors can lead to human diseases such as cancer. DNA polymerase ε (polε) is a key player in DNA replication and contains a large subunit called POLE, which possesses both a DNA polymerase domain and a 3′–5′ exonuclease domain (EXO). Mutations at the EXO domain and other missense mutations on POLE with unknown significance have been detected in a variety of human cancers. Based on cancer genome databases, Meng and colleagues (pp. 74–79) previously identified several missense mutations in POPS (pol2 family-specific catalytic core peripheral subdomain), and mutations at the conserved residues of yeast Pol2 (pol2-REL) showed reduced DNA synthesis and growth. In this issue of Genes & Development, Meng and colleagues (pp. 74–79) found unexpectedly that mutations at the EXO domain rescue the growth defects of pol2-REL. They further discovered that EXO-mediated polymerase backtracking impedes forward movement of the enzyme when POPS is defective, revealing a novel interplay between the EXO domain and POPS of Pol2 for efficient DNA synthesis. Additional molecular insight into this interplay will likely inform the impact of cancer-associated mutations found in both the EXO domain and POPS on tumorigenesis and uncover future novel therapeutic strategies.

中文翻译：

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Pol2 函数的演变故事

DNA复制非常复杂且受到高度调控，DNA复制错误可能导致癌症等人类疾病。DNA 聚合酶 ε (polε) 是 DNA 复制的关键参与者，包含一个称为 POLE 的大亚基，它同时具有 DNA 聚合酶结构域和 3'–5' 核酸外切酶结构域 (EXO)。在多种人类癌症中已检测到 EXO 结构域突变和 POLE 上其他意义不明的错义突变。基于癌症基因组数据库，Meng 及其同事（第 74-79 页）先前发现了 POPS（pol2 家族特异性催化核心外围子结构域）中的几个错义突变，并且酵母 Pol2 ( pol2-REL)保守残基的突变显示出减少DNA 合成和生长。在本期《Genes & Development》中，Meng 及其同事（第 74-79 页）意外地发现 EXO 结构域的突变挽救了pol2-REL 的生长缺陷。他们进一步发现，当 POPS 有缺陷时，EXO 介导的聚合酶回溯会阻碍酶的向前运动，揭示了 EXO 结构域和 Pol2 的 POPS 之间的新型相互作用，以实现有效的 DNA 合成。对这种相互作用的更多分子洞察可能会揭示 EXO 结构域和 POPS 中发现的癌症相关突变对肿瘤发生的影响，并揭示未来的新治疗策略。