Havlikova Jana, Dejmek Milan, Huskova Andrea, Allan Anthony, Boura Evzen, Nencka Radim, Silhan Jan
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia.
Charles University, First Faculty of Medicine, Prague, Czechia.
Commun Biol. 2025 Sep 26;8(1):1374. doi: 10.1038/s42003-025-08769-3.
Alcohol is broken down in the body into acetaldehyde, a toxic chemical that can damage DNA by creating interstrand crosslinks (AA-ICL). These crosslinks block DNA replication and threaten the stability of the genome. A rare genetic disease, Fanconi anaemia (FA), is marked by extreme sensitivity to DNA crosslinking agents, including acetaldehyde. Although the Fanconi anaemia DNA repair pathway is known to fix this type of damage, exactly how it repairs acetaldehyde crosslinks is not yet understood. Here we show that the FA nuclease Slx4-Xpf-Ercc1 (SXE) plays a key role in the repair of AA-ICL. Using a DNA replication fork with site-specific AA-ICL, we show that SXE specifically excises this crosslink, highlighting its role in the repair of alcohol-induced DNA interstrand crosslinks. Moreover, SXE performs two precise incisions flanking the AA-ICL and can similarly repair a basic-site DNA interstrand crosslink. These results expand our understanding of how the FA pathway resolves alcohol-induced DNA damage. In addition, they suggest that SXE is a versatile nuclease complex and may be involved in repairing other types of crosslinks that may activate the FA pathway.
酒精在体内会分解为乙醛，乙醛是一种有毒化学物质，可通过形成链间交联（AA-ICL）来损伤DNA。这些交联会阻碍DNA复制并威胁基因组的稳定性。一种罕见的遗传病——范可尼贫血（FA），其特征是对包括乙醛在内的DNA交联剂极度敏感。尽管已知范可尼贫血DNA修复途径能够修复这类损伤，但具体如何修复乙醛交联尚不清楚。在此我们表明，FA核酸酶Slx4-Xpf-Ercc1（SXE）在AA-ICL的修复中起关键作用。利用带有位点特异性AA-ICL的DNA复制叉，我们发现SXE能特异性切除这种交联，突显了其在修复酒精诱导的DNA链间交联中的作用。此外，SXE在AA-ICL两侧进行两次精确切割，并且同样能够修复碱性位点DNA链间交联。这些结果拓展了我们对FA途径如何解决酒精诱导的DNA损伤的理解。此外，它们表明SXE是一种多功能核酸酶复合体，可能参与修复其他可能激活FA途径的交联类型。
