Ethanol exposure increases mutation rate through error-prone polymerases
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Ethanol exposure increases mutation rate through error-prone polymerases. / Voordeckers, Karin; Colding, Camilla; Grasso, Lavinia; Pardo, Benjamin; Hoes, Lore; Kominek, Jacek; Gielens, Kim; Dekoster, Kaat; Gordon, Jonathan; Van der Zande, Elisa; Bircham, Peter; Swings, Toon; Michiels, Jan; Van Loo, Peter; Nuyts, Sandra; Pasero, Philippe; Lisby, Michael; Verstrepen, Kevin J.
In: Nature Communications, Vol. 11, 3664, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Ethanol exposure increases mutation rate through error-prone polymerases
AU - Voordeckers, Karin
AU - Colding, Camilla
AU - Grasso, Lavinia
AU - Pardo, Benjamin
AU - Hoes, Lore
AU - Kominek, Jacek
AU - Gielens, Kim
AU - Dekoster, Kaat
AU - Gordon, Jonathan
AU - Van der Zande, Elisa
AU - Bircham, Peter
AU - Swings, Toon
AU - Michiels, Jan
AU - Van Loo, Peter
AU - Nuyts, Sandra
AU - Pasero, Philippe
AU - Lisby, Michael
AU - Verstrepen, Kevin J.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - STRESS-INDUCED MUTAGENESIS
KW - DNA-REPLICATION STRESS
KW - SACCHAROMYCES-CEREVISIAE
KW - MISFOLDED PROTEINS
KW - CELL-CYCLE
KW - ALCOHOL
KW - YEAST
KW - REPAIR
KW - ACETALDEHYDE
KW - GENOME
U2 - 10.1038/s41467-020-17447-3
DO - 10.1038/s41467-020-17447-3
M3 - Journal article
C2 - 32694532
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 3664
ER -
ID: 247155573