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Acetaldehyde makes a distinct mutation signature in single-stranded DNA

View ORCID ProfileSriram Vijayraghavan, Latarsha Porcher, View ORCID ProfilePiotr A Mieczkowski, View ORCID ProfileNatalie Saini
doi: https://doi.org/10.1101/2022.03.22.485364
Sriram Vijayraghavan
1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, 29425, United States of America
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Latarsha Porcher
1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, 29425, United States of America
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Piotr A Mieczkowski
2Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, 27599, United States of America
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Natalie Saini
1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, 29425, United States of America
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  • For correspondence: sainina@musc.edu
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Abstract

Acetaldehyde (AA), a by-product of ethanol metabolism, is acutely toxic due to its ability to react with various biological molecules including DNA and proteins, which can greatly impede key processes such as replication and transcription and lead to DNA damage. As such AA is classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC). Previous in vitro studies have shown that AA generates bulky adducts on DNA, with signature guanine-centered (GG→TT) mutations. However, due to its weak mutagenicity, short chemical half-life, and the absence of powerful genetic assays, there is considerable variability in reporting the genotoxic effects of AA in vivo. Here, we used an established yeast genetic reporter system and demonstrate that AA is highly mutagenic and makes strand-biased mutations on guanines (G→T) at a high frequency on single stranded DNA (ssDNA). We further demonstrate that AA-derived mutations occur through lesion bypass on ssDNA by the translesion polymerase Polζ. Finally, we describe a unique mutation signature for AA, which we then identify in several whole-genome and -exome sequenced cancers, particularly those associated with alcohol consumption.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 22, 2022.
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Acetaldehyde makes a distinct mutation signature in single-stranded DNA
Sriram Vijayraghavan, Latarsha Porcher, Piotr A Mieczkowski, Natalie Saini
bioRxiv 2022.03.22.485364; doi: https://doi.org/10.1101/2022.03.22.485364
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Acetaldehyde makes a distinct mutation signature in single-stranded DNA
Sriram Vijayraghavan, Latarsha Porcher, Piotr A Mieczkowski, Natalie Saini
bioRxiv 2022.03.22.485364; doi: https://doi.org/10.1101/2022.03.22.485364

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