Acetaldehyde makes a distinct mutation signature in single-stranded DNA

Area of Science:

• Biochemistry
• Genetics
• Cancer Research

Background:

• Acetaldehyde (AA), a toxic ethanol metabolite, is a known carcinogen that damages DNA and proteins.
• Previous in vitro studies suggest AA causes guanine-centered mutations (GG→TT), but in vivo mutagenicity remains unclear due to technical limitations.

Purpose of the Study:

• To investigate the in vivo mutagenicity of acetaldehyde using a yeast genetic reporter system.
• To elucidate the mechanism of AA-induced DNA damage and mutation.
• To identify a unique mutation signature of AA in human cancers.

Main Methods:

• Utilized a yeast genetic reporter system to assess AA mutagenicity in vivo.
• Employed DNA sequencing to identify mutation types and patterns.
• Analyzed whole-genome and -exome data from human cancers.

Main Results:

• Acetaldehyde treatment significantly increased mutation frequency in yeast cells.
• AA induces strand-biased G→T mutations on single-stranded DNA (ssDNA).
• Mutations occur via translesion synthesis by the polymerase Polζ.
• A unique AA mutation signature was identified in alcohol-associated cancers.

Conclusions:

• Acetaldehyde is a potent mutagen in vivo, primarily acting on ssDNA.
• The translesion polymerase Polζ is involved in bypassing AA-induced DNA lesions.
• The identified AA mutation signature provides a molecular link between alcohol consumption and specific cancer types.