Induction of frameshift and base pair substitution mutations by the major DNA adduct of the endogenous carcinogen malondialdehyde

instability of repetitive sequences is a hallmark of human cancer, and its enhancement has been linked to oxidative stress. Malon-dialdehyde is an endogenous product of oxidative stress that reacts with guanine to form the exocyclic adduct, pyrimido[1,2-alpha]purin-10(3H)-one (M(1)G). We used site-specifically modified single- and double-stranded vectors to investigate the mutagenic potential of M1G in bacteria and mammalian cells. M1G induced frameshift mutations (-1 and -2) when positioned in a reiterated (CpG)(4) sequence but not when positioned in a nonreiterated sequence in Escherichia coli and in COS-7 cells. The frequency of frameshift mutations was highest when M1G was placed at the third G in the sequence. M1G induced base pair substitutions at comparable frequencies in both sequence contexts in COS-7 cells. These studies indicate that M1G, an endogenously generated product of oxidative stress, induces sequence-dependent frameshift mutations and base pair substitutions in bacteria and in mammalian cells. This finding suggests a potential role for the M(1d)G lesion in the induction of mutations commonly associated with human diseases.