Role of DNA mismatch repair and p53 in signaling induction of apoptosis byalkylating agents

All cells are unavoidably exposed to chemicals that can alkylate DNA to for m genotoxic damage. Among the various DNA lesions formed, O-6-alkylguanine lesions can be highly cytotoxic, and we recently demonstrated that O-6-meth ylguanine (O(6)MeG) and O-6-chloroethylguanine (O(6)CEG) specifically initi ate apoptosis in hamster cells. Here we show, in both hamster and human cel ls, that the MutS alpha branch of the DNA mismatch repair pathway (but not the MutS beta branch) is absolutely required for signaling the initiation o f apoptosis in response to O(6)MeGs and is partially required for signaling apoptosis in response to O(6)CEGs. Further, O(6)MeG lesions signal the sta bilization of the p53 tumor suppressor, and such signaling is also MutS alp ha-dependent. Despite this, MutS alpha-dependent apoptosis can be executed in a p53-independent manner. DNA mismatch repair status did not influence t he response of cells to other inducers of p53 and apoptosis. Thus, it appea rs that mismatch repair status, rather than p53 status, is a strong indicat or of the susceptibility of cells to alkylation-induced apoptosis. This exp erimental system will allow dissection of the signal transduction events th at couple a specific type of DNA base lesion with the final outcome of apop totic cell death.