s41467-020-17447-3.pdf (2.51 MB)
Ethanol exposure increases mutation rate through error-prone polymerases.
journal contributionposted on 2020-10-22, 10:52 authored by 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
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.
Crick (Grant ID: 10202, Grant title: Van Loo FC001202)