Multiple DNA repair pathways prevent acetaldehyde-induced mutagenesis in yeast

Area of Science:

• Molecular Biology
• Genetics
• Toxicology

Background:

• Acetaldehyde, a metabolite of alcohol and component of tobacco smoke, is genotoxic and linked to cancer.
• Defects in acetaldehyde clearance increase susceptibility to alcohol-associated cancers, with a specific mutation signature observed.
• The DNA repair pathways preventing acetaldehyde-induced mutagenesis are not well understood.

Purpose of the Study:

• To identify DNA repair pathways that prevent acetaldehyde-induced mutagenesis using Saccharomyces cerevisiae.
• To elucidate the mechanisms underlying acetaldehyde-induced DNA damage and mutation.

Main Methods:

• Systematic deletion of genes in major DNA repair pathways in yeast.
• Assessing the impact of gene deletions on acetaldehyde-induced mutagenesis.
• Whole-genome sequencing of mutated yeast isolates.
• Investigating the role of specific DNA repair pathways and polymerases.

Main Results:

• Loss of nucleotide excision repair significantly increased acetaldehyde mutagenesis.
• Base excision repair and DNA protein crosslink repair pathways modulated mutagenesis.
• Mismatch repair, homologous recombination, and postreplication repair were dispensable.
• Acetaldehyde-induced mutations showed a C→A change signature, diagnostic of exposure.
• Lesions likely form on the leading strand, implicating Pol epsilon.

Conclusions:

• Nucleotide excision repair is the primary pathway preventing acetaldehyde-induced mutagenesis.
• Multiple DNA repair pathways coordinate to mitigate acetaldehyde's genotoxic effects.
• The findings provide insights into cancer prevention related to alcohol and smoking.