α,β-Unsaturated aldehydes react with nucleic acid bases to form exocyclic adducts that block Watson-Crick base-pairing and impede replication by DNA polymerases. Exocyclic adducts are bypassed by translesion polymerases. a process that induces base-pair substitutions and frameshift mutations. The adducts are repaired to differing extents by nucleotide excision repair and base excision repair. Certain exocyclic adducts retain electrophilic character while present in DNA and participate in cross-linking and hydrolytic ring-opening. For example, the pyrimidopurinone adduct, M1dG, derived from the reaction of base propenals with deoxyguanosine residues, ring-opens to N2-oxopropenyl-deoxyguanosine when positioned opposite deoxycytidine residues in DNA. M1dG also undergoes enzymatic oxidation by AlkB to form deoxyguanosine thereby directly repairing the lesion. In addition, M1dG has been found to be enzymatically oxidized in genomic DNA in a range of human cell lines to 6-oxo-M1dG. M1dG present in mitochondrial DNA is not oxidized to 6-oxo-M1dG. DNA adducts derived from a,β-unsaturated aldehydes are quantitatively significant endogenous lesions in humans and rodents and they exhibit a range of chemical reactions within the genome. This chemical reactivity leads to a diversity of biological outcomes that modulate mutagenesis and repair.

Chemical biology of DNA damage by α,β-unsaturated aldehydes

254th National Meeting (2017)

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