Mismatch repair processing of carcinogen-DNA adducts triggers apoptosis

Citation
Jx. Wu et al., Mismatch repair processing of carcinogen-DNA adducts triggers apoptosis, MOL CELL B, 19(12), 1999, pp. 8292-8301
Citations number
77
Categorie Soggetti
Molecular Biology & Genetics
Journal title
MOLECULAR AND CELLULAR BIOLOGY
ISSN journal
02707306 → ACNP
Volume
19
Issue
12
Year of publication
1999
Pages
8292 - 8301
Database
ISI
SICI code
0270-7306(199912)19:12<8292:MRPOCA>2.0.ZU;2-3
Abstract
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.