Multiple DNA repair pathways prevent acetaldehyde-induced mutagenesis in yeast.

IF 3.3 3区 生物学 Q2 GENETICS & HEREDITY
Genetics Pub Date : 2024-12-21 DOI:10.1093/genetics/iyae213
Latarsha Porcher, Sriram Vijayraghavan, Yashvi Patel, Samuel Becker, Thomas Blouin, James McCollum, Piotr A Mieczkowski, Natalie Saini
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引用次数: 0

Abstract

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 (NER) had the largest effect on acetaldehyde mutagenesis. In addition, base excision repair (BER), as well as DNA protein crosslink (DPC) repair pathways were involved in modulating acetaldehyde mutagenesis, while mismatch repair (MMR), homologous recombination (HR) and post replication repair are dispensable for acetaldehyde mutagenesis. Acetaldehyde-induced mutations in an NER-deficient (Δrad1) background were dependent on translesion synthesis as well as DNA inter-strand crosslink (ICL) 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.

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来源期刊
Genetics
Genetics GENETICS & HEREDITY-
CiteScore
6.90
自引率
6.10%
发文量
177
审稿时长
1.5 months
期刊介绍: GENETICS is published by the Genetics Society of America, a scholarly society that seeks to deepen our understanding of the living world by advancing our understanding of genetics. Since 1916, GENETICS has published high-quality, original research presenting novel findings bearing on genetics and genomics. The journal publishes empirical studies of organisms ranging from microbes to humans, as well as theoretical work. While it has an illustrious history, GENETICS has changed along with the communities it serves: it is not your mentor''s journal. The editors make decisions quickly – in around 30 days – without sacrificing the excellence and scholarship for which the journal has long been known. GENETICS is a peer reviewed, peer-edited journal, with an international reach and increasing visibility and impact. All editorial decisions are made through collaboration of at least two editors who are practicing scientists. GENETICS is constantly innovating: expanded types of content include Reviews, Commentary (current issues of interest to geneticists), Perspectives (historical), Primers (to introduce primary literature into the classroom), Toolbox Reviews, plus YeastBook, FlyBook, and WormBook (coming spring 2016). For particularly time-sensitive results, we publish Communications. As part of our mission to serve our communities, we''ve published thematic collections, including Genomic Selection, Multiparental Populations, Mouse Collaborative Cross, and the Genetics of Sex.
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