The DNA mismatch repair pathway is well known for its role in correcting bi
osynthetic errors of DNA replication. We report here a novel role for misma
tch repair in signaling programmed cell death in response to DNA damage ind
uced by chemical carcinogens, Cells proficient in mismatch repair were high
ly 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 treat
ment with chemical carcinogens, the apoptotic response is dependent on a fu
nctional mismatch repair system. By analyzing p53 expression in several pai
rs of cell lines, we found that the mismatch repair-dependent apoptotic res
ponse was mediated through both p53 dependent and p53-independent pathways,
In vitro biochemical studies demonstrated that the human mismatch recognit
ion proteins hMutS alpha and hMutS beta efficiently recognized DNA damage i
nduced by chemical carcinogens, suggesting a direct participation of mismat
ch repair proteins in mediating the apoptotic response. Taken together, the
se studies further elucidate the mechanism by which mismatch repair deficie
ncy predisposes to cancer, i.e., the deficiency not only causes a failure t
o repair mismatches generated during DNA metabolism but also fails to direc
t damaged and mutation-prone cells to commit suicide.