Mutation signatures specific to DNA alkylating agents in yeast and cancers

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• Alkylation is a common DNA damage, but the substrate preferences of SN1 and SN2 alkylating agents remain poorly understood.
• Understanding these preferences is crucial for deciphering mutation signatures in various cancers.

Purpose of the Study:

• To investigate the substrate specificity and mutation signatures of SN1 and SN2 DNA alkylating agents.
• To identify conserved alkylation mutagenesis signatures across different species and cancer types.

Main Methods:

• Utilized engineered yeast strains for large-scale single-stranded DNA (ssDNA) production.
• Analyzed mutation spectra and signatures induced by SN1 and SN2 alkylating agents in yeast.
• Compared yeast-derived signatures with whole-exome and whole-genome sequencing data from human cancers.

Main Results:

• SN1-type agents preferentially mutagenize double-stranded DNA (dsDNA), with conserved mutation signatures in yeast, mice, and human cancers.
• SN2-type agents preferentially mutagenize ssDNA in yeast, and their signatures are detectable in lung, head and neck cancers, and tumors from exposed patients.
• Higher SN2-type alkylation signature loads were observed in lung tumors from smokers, suggesting a role for cigarette carcinogens.

Conclusions:

• Developed specific mutation signatures for SN1 and SN2 alkylation mutagenesis.
• Demonstrated the conserved nature of SN1-type alkylation signatures across species.
• Provided evidence for SN2-type alkylating agents contributing to mutagenesis in human cancers, particularly in smokers.