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Ethanol exposure increases mutation rate through error-prone polymerases

Year: 2020
Type: article
Abstract: Ethanol is a ubiquitous environmental stressor that is toxic to all lifeforms. Here, we use the model eukaryote Saccharomyces cerevisiae to show that exposure to sublethal ethanol concentrations causes DNA replication stress and an increased mutation rate. Specifically, we find that ethanol slows down replication and affects localization of Mrc1, a conserved protein that helps stabilize the replisome. In addition, ethanol exposure also results in the recruitment of error-prone DNA polymerases to the replication fork. Interestingly, preventing this recruitment through mutagenesis of the PCNA/Pol30 polymerase clamp or deleting specific error-prone polymerases abolishes the mutagenic effect of ethanol. Taken together, this suggests that the mutagenic effect depends on a complex mechanism, where dysfunctional replication forks lead to recruitment of error-prone polymerases. Apart from providing a general mechanistic framework for the mutagenic effect of ethanol, our findings may also provide a route to better understand and prevent ethanol-associated carcinogenesis in higher eukaryotes.
DOI: 10.1038/s41467-020-17447-3
Authors: Karin Voordeckers, Camilla Colding, Lavinia Grasso, Benjamin Pardo, Lore Hoes, Jacek Kominek, Kim Gielens, Kaat Dekoster, Jonathan Gordon, Elisa Van der Zande, Peter Bircham, Toon Swings, Jan Michiels, Peter Van Loo, Sandra Nuyts, Philippe Pasero, Michael Lisby, Kevin J. Verstrepen
Institutions: VIB-KU Leuven Center for Microbiology, KU Leuven, University of Copenhagen, Centre National de la Recherche Scientifique, Université de Montpellier, Institut de Génétique Humaine, Universitair Ziekenhuis Leuven, University of Wisconsin–Madison, The Francis Crick Institute
Language: English
Open Access status: gold
Estimated APC paid: $5,380
Funders: Villum Fonden, Wellcome Trust, Francis Crick Institute, Cancer Research UK, Human Frontier Science Program, Agence Nationale de la Recherche, Technische Universiteit Delft, Fonds Wetenschappelijk Onderzoek, KU Leuven, Ligue Contre le Cancer, Vlaams Instituut voor Biotechnologie, Institut National Du Cancer, Vlaamse regering, Medical Research Council
Awards: G154923120, G1739813011, G1879383613, G2264628962, Identifying molecular mechanisms underlying the effects of ethanol on eukaryotic genome instability, Natural metabolite variation: linking genotype to phenotype., G4653762689, G4774273565, G6137580159, Effect of ethanol on eukaryotic genome stability: identification of molecular mechanisms, G7884127298
OpenAlex ID: W3045396963
FWCI: 1.787
Cites: 86
Cited by: 63
Related to: 10