The Escherichia coli MutS DNA mismatch binding protein specifically binds 0-methylguanine DNA lesions

DNA mismatch repair defects in certain cell types confer resistance to the cytotoxic effects of alkylating agents, suggesting that a normally functioning DNA mismatch repair pathway can actually mediate alkylation-induced cell death. In eukaryotic cells this phenomenon is only observed in cells lacking adequate DNA methyltransferase for the repair of 0*-methylguanine (O*MeG) DNA lesions. It has been proposed that O*MeG may act as a substrate for DNA mismatch repair when paired with cytosine and when mispaired with thymine and that repeated futile DNA mismatch repair at 0*MeG DNA lesions is cytotoxic Here we show that the Escherichia coli MutS DNA mismatch repair binding protein does indeed bind specifically to 0*MeG DNA lesions. In contrast, MutS does not bind DNA containing another 0-alkylated base, namely Omethylthymine, or another kind of modified guanine, namely 8-oxoguanine. These results provide direct biochemical evidence for the involvement of DNA mismatch repair in specifically processing O*MeG DNA lesions.