M1dG is a major endogenous DNA adduct formed by reaction of deoxyguanosine residues with oxopropenylating agents derived from DNA and lipid oxidation. It is detectable in human genomic DNA and its levels in mitochondrial DNA are significantly higher than in genomic DNA. M1dG induces deletions as well as transitions to A and transversions to T when it is replicated in bacterial or mammalian cells. M1dG is repaired by nucleotide excision repair and appears to be recognized by proteins involved in mismatch repair. Our laboratory discovered the existence of an enzymatic activity in the nucleus that oxidizes M1dG to a 6-oxo-derivative. The kinetics of oxidation of M1dG in the genome suggest it occurs more rapidly than nucleotide excision repair. 6-Oxo-M1dG was incorporated into oligonucleotides by chemical synthesis and annealed to primers for in vitro replication. The presence of this adduct blocked DNA replication by the translesion polymerases, eta, kappa and iota to varying extents. The chemical properties of 6-oxo-M1dG and its ability to block DNA replication suggest it is more genotoxic and mutagenic than M1dG. The competition between nucleotide excision repair and genomic oxidation of M1dG may be a major determinant of mutagenic consequences of its in vivo occurrence.

Competition between repair and oxidation of the endogenous DNA adduct, 3(2-deoxy-β-D-erythro-pentofuranosyl)pyrimido[1,2-α]purin-10(3H)-one (M1dG)

2019 Fall National Meeting

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