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 i n the cellular response to certain types of DNA damage, and genetic de fects in this pathway are known to confer resistance to the cytotoxic effects of DNA-methylating agents, Such observations suggest that in a ddition to their ability to recognize DNA base-pairing errors, members of the MutS family may also respond to genetic lesions produced by DN A damage, We show that the human mismatch recognition activity MutS al pha recognizes several types of DNA lesion including the 1,2-intrastra nd d(GpG) crosslink produced by cis-diamminedichloroplatinum(II), as w ell as base pairs between O-6-methylguanine and thymine or cytosine, o r between O-4-methylthymine and adenine, However, the protein fails to recognize 1,3-intrastrand adduct produced by trans-diamminedichloropl atinum (II) at a d(GpTpG) sequence. These observations imply direct in volvement of the mismatch repair system in the cytotoxic effects of DN A-methylating agents and suggest that recognition of 1,2-intrastrand c is-diamminedichloroplatinum(ll) adducts by MutS alpha may be involved in the cytotoxic action of this chemotherapeutic agent.