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Acetaldehyde makes a distinct mutation signature in single-stranded DNA
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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303387/ https://www.ncbi.nlm.nih.gov/pubmed/35776120 http://dx.doi.org/10.1093/nar/gkac570 |
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author | Vijayraghavan, Sriram Porcher, Latarsha Mieczkowski, Piotr A Saini, Natalie |
author_facet | Vijayraghavan, Sriram Porcher, Latarsha Mieczkowski, Piotr A Saini, Natalie |
author_sort | Vijayraghavan, Sriram |
collection | PubMed |
description | 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 mutagenic effects of AA in vivo. Here, we used an established yeast genetic reporter system and demonstrate that AA treatment is highly mutagenic to cells and leads to 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. Our study proposes a key mechanism underlying carcinogenesis by acetaldehyde—mutagenesis of single-stranded DNA. |
format | Online Article Text |
id | pubmed-9303387 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-93033872022-07-22 Acetaldehyde makes a distinct mutation signature in single-stranded DNA Vijayraghavan, Sriram Porcher, Latarsha Mieczkowski, Piotr A Saini, Natalie Nucleic Acids Res Genome Integrity, Repair and Replication 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 mutagenic effects of AA in vivo. Here, we used an established yeast genetic reporter system and demonstrate that AA treatment is highly mutagenic to cells and leads to 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. Our study proposes a key mechanism underlying carcinogenesis by acetaldehyde—mutagenesis of single-stranded DNA. Oxford University Press 2022-07-01 /pmc/articles/PMC9303387/ /pubmed/35776120 http://dx.doi.org/10.1093/nar/gkac570 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Genome Integrity, Repair and Replication Vijayraghavan, Sriram Porcher, Latarsha Mieczkowski, Piotr A Saini, Natalie Acetaldehyde makes a distinct mutation signature in single-stranded DNA |
title | Acetaldehyde makes a distinct mutation signature in single-stranded DNA |
title_full | Acetaldehyde makes a distinct mutation signature in single-stranded DNA |
title_fullStr | Acetaldehyde makes a distinct mutation signature in single-stranded DNA |
title_full_unstemmed | Acetaldehyde makes a distinct mutation signature in single-stranded DNA |
title_short | Acetaldehyde makes a distinct mutation signature in single-stranded DNA |
title_sort | acetaldehyde makes a distinct mutation signature in single-stranded dna |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303387/ https://www.ncbi.nlm.nih.gov/pubmed/35776120 http://dx.doi.org/10.1093/nar/gkac570 |
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