荷兰哈勃雷赫特研究所Puck Knipscheer和英国牛津大学Ketan J. Patel合作发现酒精造成的DNA交联可通过两种不同的机理修复。该研究于2020年3月4日发表于国际学术期刊《自然》杂志上。

他们生成乙醛诱导的DNA链间交联，并确定它们在非洲爪蟾卵提取物中的修复机制。他们发现两个复制耦联途径可修复这些病变。第一个是FA途径，该途径使用切除进行操作，这类似于修复由化学治疗药物顺铂引起的链间交联的机制。然而，与顺铂诱导的交联修复相比，乙醛诱导的交联修复导致突变频率增加和突变谱改变。第二种修复机制需要复制叉融合，但不涉及DNA切口，而是乙醛交联本身被破坏。Y家族DNA聚合酶REV1完成交联的修复，最终形成独特的突变谱。这些结果表明由内源性和酒精造成的代谢产物引起的DNA链间交联修复途径，并确定了与切除无关的机制。

研究人员表示，乙醛是一种高反应性，对DNA有害的代谢产物，是在饮酒后产生的。乙醛的排毒功能受损在亚裔人群中很普遍，且酒精相关的癌症与其有关。DNA交联修复可保护细胞免受乙醛诱导的损伤，当此途径受损时会引起范可尼贫血（FA），这种疾病导致无法产生血细胞并易患癌症。乙醛解毒和FA途径的联合失活诱导的突变，会加速恶性肿瘤并引起血液干细胞的快速损耗。然而，乙醛引起的DNA损伤的性质及如何修复仍是一个关键问题。

附：英文原文

Title: Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms

Author: Michael R. Hodskinson, Alice Bolner, Koichi Sato, Ashley N. Kamimae-Lanning, Koos Rooijers, Merlijn Witte, Mohan Mahesh, Jan Silhan, Maya Petek, David M. Williams, Jop Kind, Jason W. Chin, Ketan J. Patel, Puck Knipscheer

Issue&Volume: 2020-03-04

Abstract: Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption1. Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers1,2. Cells are protected against acetaldehyde-induced damage by DNA crosslink repair, which when impaired causes Fanconi anaemia (FA), a disease resulting in failure to produce blood cells and a predisposition to cancer3,4. The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells5,6,7. However, the nature of the DNA damage induced by acetaldehyde and how this is repaired remains a key question. Here we generate acetaldehyde-induced DNA interstrand crosslinks and determine their repair mechanism in Xenopus egg extracts. We find that two replication-coupled pathways repair these lesions. The first is the FA pathway, which operates using excision—analogous to the mechanism used to repair the interstrand crosslinks caused by the chemotherapeutic agent cisplatin. However, the repair of acetaldehyde-induced crosslinks results in increased mutation frequency and an altered mutational spectrum compared with the repair of cisplatin-induced crosslinks. The second repair mechanism requires replication fork convergence, but does not involve DNA incisions—instead the acetaldehyde crosslink itself is broken. The Y-family DNA polymerase REV1 completes repair of the crosslink, culminating in a distinct mutational spectrum. These results define the repair pathways of DNA interstrand crosslinks caused by an endogenous and alcohol-derived metabolite, and identify an excision-independent mechanism.

DOI: 10.1038/s41586-020-2059-5

Source: https://www.nature.com/articles/s41586-020-2059-5