All cells are unavoidably exposed to chemicals that can alkylate DNA to form genotoxic damage. Among the various DNA lesions formed, O6-alkylguanine lesions can be highly cytotoxic, and we recently demonstrated that O6- methylguanine (O6MeG) and O6-chloroethylguanine (O6CEG) specifically initiate apoptosis in hamster cells. Here we show, in both hamster and human cells, that the MutSα branch of the DNA mismatch repair pathway (but not the MutSβ branch) is absolutely required for signaling the initiation of apoptosis in response to O6MeGs and is partially required for signaling apoptosis in response to O6CEGs. Further, O6MeG lesions signal the stabilization of the p53 tumor suppressor, and such signaling is also MutSα- dependent. Despite this, MutSα-dependent apoptosis can be executed in a p53- independent manner. DNA mismatch repair status did not influence the response of cells to other inducers of p53 and apoptosis. Thus, it appears that mismatch repair status, rather than p53 status, is a strong indicator of the susceptibility of cells to alkylation-induced apoptosis. This experimental system will allow dissection of the signal transduction events that couple a specific type of DNA base lesion with the final outcome of apoptotic cell death.
|Number of pages
|Proceedings of the National Academy of Sciences of the United States of America
|Published - Sep 14 1999
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