TY - JOUR
T1 - Mismatch repair processing of carcinogen-DNA adducts triggers apoptosis
AU - Wu, Jianxin
AU - Gu, Liya
AU - Wang, Huixian
AU - Geacintov, Nicholas E.
AU - Li, Guo Min
PY - 1999/12
Y1 - 1999/12
N2 - 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 hMutSα and hMutSβ 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.
AB - 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 hMutSα and hMutSβ 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.
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U2 - 10.1128/MCB.19.12.8292
DO - 10.1128/MCB.19.12.8292
M3 - Article
C2 - 10567554
AN - SCOPUS:0033513097
SN - 0270-7306
VL - 19
SP - 8292
EP - 8301
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 12
ER -