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. Malondialdehyde is an endogenous product of oxidative stress that reacts with guanine to form the exocyclic adduct, pyrimido[1,2- α]purin-10(3H)-one (M₁G). 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 M₁G lesion in the induction of mutations commonly associated with human diseases.