Methylglyoxal mutagenizes single-stranded DNA via Rev1-associated slippage and mispairing

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Methylglyoxal (MG) is a reactive aldehyde from metabolism and external sources.
• MG exposure links to diseases, including cancers, due to DNA and protein damage.
• The in vivo mutagenicity of MG across the genome is not well understood.

Purpose of the Study:

• To investigate genome-wide methylglyoxal (MG) mutagenicity in vivo.
• To understand the mechanisms underlying MG-induced DNA damage and mutations.
• To assess the relevance of MG-associated mutations in human cancers.

Main Methods:

• Utilizing yeast as a model organism to study MG mutagenesis.
• Assessing MG mutagenicity in the presence and absence of the glyoxalase Glo1.
• Employing aminoguanidine to quench aldehyde activity.
• Identifying mutation mechanisms, including strand slippage and mispairing.
• Analyzing tumor datasets for enriched MG-associated mutations.

Main Results:

• MG robustly mutagenizes single-stranded DNA in a guanine-centered motif.
• MG mutagenesis is significantly increased without glyoxalase Glo1 and reduced with aminoguanidine.
• Strand slippage and mispairing are the primary mechanisms for MG mutations.
• The translesion polymerase Rev1 is crucial for MG mutagenesis.
• A key MG-associated mutation is enriched in human tumor datasets.

Conclusions:

• Methylglyoxal (MG) is a significant mutagen contributing to genome instability.
• Understanding MG's mutagenic pathways, involving strand slippage and Rev1, is vital.
• MG-induced mutations may play a role in cancer development.