Human MutS alpha recognizes damaged DNA base pairs containing O-6-methylguanine, O-4-methylthymine, or the cisplatin-d(GpG) adduct

Bacterial and mammalian mismatch repair systems have been implicated in the cellular response to certain types of DNA damage, and genetic defects in this pathway are known to confer resistance to the cytotoxic effects of DNA-methylating agents, Such observations suggest that in addition to their ability to recognize DNA base-pairing errors, members of the MutS family may also respond to genetic lesions produced by DNA damage, We show that the human mismatch recognition activity MutS alpha recognizes several types of DNA lesion including the 1,2-intrastrand d(GpG) crosslink produced by cis-diamminedichloroplatinum(II), as well as base pairs between O-6-methylguanine and thymine or cytosine, or between O-4-methylthymine and adenine, However, the protein fails to recognize 1,3-intrastrand adduct produced by trans-diamminedichloroplatinum (II) at a d(GpTpG) sequence. These observations imply direct involvement of the mismatch repair system in the cytotoxic effects of DNA-methylating agents and suggest that recognition of 1,2-intrastrand cis-diamminedichloroplatinum(ll) adducts by MutS alpha may be involved in the cytotoxic action of this chemotherapeutic agent.