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Investigating the Metabolism of a Major Peroxidation DNA adduct, M1dG, in the Genome

Chronic inflammation results in increased production of reactive oxygen species (ROS), which can oxidize cellular molecules including lipids and DNA. Our laboratory has shown that 3‐(2‐deoxy‐b‐D‐erythro‐pentofuranosyl)pyrimido[1,2‐a]purin‐10(3H)‐one (M1dG) is the most abundant DNA adduct formed from the lipid peroxidation product, malondialdehyde, or the DNA peroxidation product, base propenal. M1dG is mutagenic in bacterial and mammalian cells and is repaired via the nucleotide excision repair system. Here, we report that M1dG levels in intact nuclear DNA were increased from basal levels of 1 adduct per 108 nucleotides to 2 adducts per 106 nucleotides following adenine propenal treatment of RKO, HEK293 or HepG2 cells. We also found that M1dG in genomic DNA was oxidized in a time‐dependent fashion to a single product, 6‐oxo‐M1dG, (to ~ 5 adducts per 107 nucleotides) and that this oxidation correlated with a decline in M1dG levels. Investigations in RAW264.7 macrophages indicate the presence of high basal levels of M1dG (1 adduct per 106 nucleotides) and the endogenous formation of 6‐oxo‐M1dG. Interestingly, in all cell lines investigated, 6‐oxo‐M1dG was not observed in mitochondrial DNA. Basal levels of M1dG in the mitochondria were found to be approximately two orders of magnitude higher (~ 1 adduct per 106 nucleotides) than those observed in nuclear DNA and were increased with electrophilic stimulation. Further studies, in all the investigated cell lines, indicated a correlation between M1dG levels and oxidative stress in the mitochondrion. This is the first report of M1dG in mitochondrial DNA in intact cells and it has significant implications for understanding the role of inflammation in DNA damage, mutagenesis and repair.