Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents.
All cells are unavoidably exposed to chemicals that can alkylate DNA to form genotoxic damage. Among the various DNA lesions formed, O(6)-alkylguanine lesions can be highly cytotoxic, and we recently demonstrated that O(6)-methylguanine (O(6)MeG) and O(6)-chloroethylguanine (O(6)CEG) specifically initiate apoptosis in hamster cells. Here we show, in both hamster and human cells, that the MutSalpha branch of the DNA mismatch repair pathway (but not the MutSbeta branch) is absolutely required for signaling the initiation of 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 stabilization of the p53 tumor suppressor, and such signaling is also MutSalpha-dependent. Despite this, MutSalpha-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.
Hickman
M J
MJ
Department of Cancer Cell Biology, Toxicology Division, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
Samson
L D
LD
D000251:Adenosine Triphosphatases; D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D002273:Carcinogens / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D029968:Escherichia coli Proteins; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D051719:MutS DNA Mismatch-Binding Protein; D009153:Mutagens / Q000494:pharmacology; D011839:Radiation, Ionizing; D015398:Signal Transduction; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000477:Alkylating Agents; D001426:Bacterial Proteins; D002273:Carcinogens; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D008769:Methylnitronitrosoguanidine; C028317:7-(beta-chloroethyl)guanine; D006147:Guanine; D000251:Adenosine Triphosphatases; D051719:MutS DNA Mismatch-Binding Protein; C497175:MutS protein, E coli; D002330:Carmustine