The role of mismatch repair in DNA damage-induced apoptosis

DNA mismatch repair plays a critical role in maintaining genomic integrity. Defects in human mismatch repair are the primary cause of certain types of cancer, including hereditary nonpolyposis colorectal cancer. In the past, the ability of mismatch repair proteins to con cct DNA mismatches that occu r during DNA replication, repair, and recombination was considered the prim ary mechanism by which it contributes to genomic stability. However, increa sing evidence supports the idea that the mismatch repair system also contri butes to genome stability by stimulating DNA damage-induced apoptosis as pa rt of the cytotoxic response to physical and chemical agents. MutS/MutL hom ologues mediate the process of apoptosis by binding Irt DNA adducts and eit her provoking futile repair events or blocking steps in DNA metabolism (i.e ., DNA replication and/or repair). This damage recognition step by mismatch repair (MMR) proteins stimulates a signaling cascade for apoptosis, result ing in activation of protein kinase(s) that phosphorylate p53 and/or the re lated protein p73. Activated p53 and p73 in turn transmit a signal to the a poptotic machinery to execute cell death. The goal of this commentary is to discuss the molecular mechanism(s) by which mismatch repair proteins stimu late apoptosis.