Ethanol exposure increases mutation rate through error-prone polymerases

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 () and Kevin J. Verstrepen ()
Additional contact information
Karin Voordeckers: VIB-KU Leuven Center for Microbiology
Camilla Colding: University of Copenhagen
Lavinia Grasso: Institut de Génétique Humaine, CNRS and Université de Montpellier, 141 rue de la Cardonille
Benjamin Pardo: Institut de Génétique Humaine, CNRS and Université de Montpellier, 141 rue de la Cardonille
Lore Hoes: VIB-KU Leuven Center for Microbiology
Jacek Kominek: VIB-KU Leuven Center for Microbiology
Kim Gielens: VIB-KU Leuven Center for Microbiology
Kaat Dekoster: VIB-KU Leuven Center for Microbiology
Jonathan Gordon: VIB-KU Leuven Center for Microbiology
Elisa Van der Zande: VIB-KU Leuven Center for Microbiology
Peter Bircham: VIB-KU Leuven Center for Microbiology
Toon Swings: KU Leuven
Jan Michiels: KU Leuven
Peter Van Loo: The Francis Crick Institute
Sandra Nuyts: KU Leuven
Philippe Pasero: Institut de Génétique Humaine, CNRS and Université de Montpellier, 141 rue de la Cardonille
Michael Lisby: University of Copenhagen
Kevin J. Verstrepen: VIB-KU Leuven Center for Microbiology

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17447-3

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DOI: 10.1038/s41467-020-17447-3

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