Mismatch repair processing of carcinogen-DNA adducts triggers apoptosis.
The DNA mismatch repair pathway is well known for its role in correcting biosynthetic errors of DNA replication. We report here a novel role for mismatch repair in signaling programmed cell death in response to DNA damage induced by chemical carcinogens. Cells proficient in mismatch repair were highly sensitive to the cytotoxic effects of chemical carcinogens, while cells defective in either human MutS or MutL homologs were relatively insensitive. Since wild-type cells but not mutant cells underwent apoptosis upon treatment with chemical carcinogens, the apoptotic response is dependent on a functional mismatch repair system. By analyzing p53 expression in several pairs of cell lines, we found that the mismatch repair-dependent apoptotic response was mediated through both p53-dependent and p53-independent pathways. In vitro biochemical studies demonstrated that the human mismatch recognition proteins hMutSalpha and hMutSbeta efficiently recognized DNA damage induced by chemical carcinogens, suggesting a direct participation of mismatch repair proteins in mediating the apoptotic response. Taken together, these studies further elucidate the mechanism by which mismatch repair deficiency predisposes to cancer, i.e., the deficiency not only causes a failure to repair mismatches generated during DNA metabolism but also fails to direct damaged and mutation-prone cells to commit suicide.
Wu
J
J
Department of Pathology and Laboratory Medicine, Markey Cancer Center, University of Kentucky Medical Center, Lexington, Kentucky 40536, USA.
Gu
L
L
Wang
H
H
Geacintov
N E
NE
Li
G M
GM
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D017209:Apoptosis; D020137:Base Pair Mismatch; D002273:Carcinogens; D002460:Cell Line; D018736:DNA Adducts; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D019906:Nuclear Magnetic Resonance, Biomolecular; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D002273:Carcinogens; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C094443:G-T mismatch-binding protein; C078444:MSH3 protein, human; C043931:benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; C497172:MSH2 protein, human; C421109:multidrug resistance-associated protein 1