RT Journal Article
SR Electronic
T1 Acetaldehyde makes a distinct mutation signature in single-stranded DNA
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.03.22.485364
DO 10.1101/2022.03.22.485364
A1 Sriram Vijayraghavan
A1 Latarsha Porcher
A1 Piotr A Mieczkowski
A1 Natalie Saini
YR 2022
UL http://biorxiv.org/content/early/2022/03/22/2022.03.22.485364.abstract
AB 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 StatementThe authors have declared no competing interest.