The Escherichia coli MutS DNA mismatch binding protein specifically binds O(6)-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 O6-methylguanine (O6MeG) DNA lesions. It has been proposed that O6MeG 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 O6MeG DNA lesions is cytotoxic. Here we show that the Escherichia coli MutS DNA mismatch repair binding protein does indeed bind specifically to O6MeG DNA lesions. In contrast, MutS does not bind DNA containing another O-alkylated base, namely O4-methylthymine, 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 O6MeG DNA lesions.