Porcher Latarsha, Vijayraghavan Sriram, Patel Yashvi, Becker Samuel, Blouin Thomas, McCollum James, Mieczkowski Piotr A, Saini Natalie
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Genetics. 2025 Apr 17;229(4). doi: 10.1093/genetics/iyae213.
Acetaldehyde is the primary metabolite of alcohol and is present in many environmental sources, including tobacco smoke. Acetaldehyde is genotoxic, whereby it can form DNA adducts and lead to mutagenesis. Individuals with defects in acetaldehyde clearance pathways have increased susceptibility to alcohol-associated cancers. Moreover, a mutation signature specific to acetaldehyde exposure is widespread in alcohol- and smoking-associated cancers. However, the pathways that repair acetaldehyde-induced DNA damage and thus prevent mutagenesis are vaguely understood. Here, we used Saccharomyces cerevisiae to delete genes in each of the major DNA repair pathways to identify those that alter acetaldehyde-induced mutagenesis. We observed that loss of functional nucleotide excision repair had the largest effect on acetaldehyde mutagenesis. In addition, base excision repair and DNA protein crosslink repair pathways were involved in modulating acetaldehyde mutagenesis, while mismatch repair, homologous recombination, and postreplication repair are dispensable for acetaldehyde mutagenesis. Acetaldehyde-induced mutations in a nucleotide excision repair-deficient (Δrad1) background were dependent on translesion synthesis and DNA interstrand crosslink repair. Moreover, whole-genome sequencing of the mutated isolates demonstrated an increase in C→A changes coupled with an enrichment of gCn→A changes, which is diagnostic of acetaldehyde exposure in yeast and in human cancers. Finally, downregulation of the leading strand replicative polymerase Pol epsilon, but not the lagging strand polymerase, resulted in increased acetaldehyde mutagenesis, indicating that lesions are likely formed on the leading strand. Our findings demonstrate that multiple DNA repair pathways coordinate to prevent acetaldehyde-induced mutagenesis.
乙醛是酒精的主要代谢产物，存在于许多环境来源中，包括烟草烟雾。乙醛具有基因毒性，可形成DNA加合物并导致诱变。乙醛清除途径存在缺陷的个体对酒精相关癌症的易感性增加。此外，乙醛暴露特有的突变特征在酒精和吸烟相关癌症中广泛存在。然而，修复乙醛诱导的DNA损伤从而防止诱变的途径尚不清楚。在这里，我们使用酿酒酵母删除每个主要DNA修复途径中的基因，以确定那些改变乙醛诱导诱变的基因。我们观察到，功能性核苷酸切除修复的缺失对乙醛诱变的影响最大。此外，碱基切除修复和DNA蛋白交联修复途径参与调节乙醛诱变，而错配修复、同源重组和复制后修复对于乙醛诱变是可有可无的。在核苷酸切除修复缺陷（Δrad1）背景下，乙醛诱导的突变依赖于跨损伤合成和DNA链间交联修复。此外，对突变菌株的全基因组测序表明，C→A变化增加，同时gCn→A变化富集，这是酵母和人类癌症中乙醛暴露的诊断特征。最后，前导链复制聚合酶Pol ε的下调而非滞后链聚合酶的下调导致乙醛诱变增加，表明损伤可能在前导链上形成。我们的研究结果表明，多种DNA修复途径协同作用以防止乙醛诱导的诱变。
