Nucleic Acids Research, 2003, Vol. 31, No. 22 6428-6434
© 2003 Oxford University Press
Article |
In vitro and in vivo modulations of benzo[c]phenanthrene–DNA adducts by DNA mismatch repair system
1 Markey Cancer Center and Department of Pathology, 2 Department of Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40536, USA and 3 Biochemical Institute for Environmental Carcinogens, Grosshansdorf, Germany
*To whom correspondence should be addressed. Tel: +1 859 257 7053; Fax: +1 859 323 2094; Email: gmli{at}uky.edu
Present addresses:
Jianxin Wu, The Capital Institute of Pediatrics, Beijing, China
Jin Yu, Hong Zhu and Mark S. Kindy, Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC, USA
Benzo[c]phenanthrene dihydrodiol epoxide (B[c] PhDE) is well known as an important environmental chemical carcinogen that preferentially modifies DNA in adenine residues. However, the molecular mechanism by which B[c]PhDE induces tumorigenesis is not fully understood. In this report, we demonstrate that DNA mismatch repair (MMR), a genome maintenance system, plays an important role in B[c]PhDE-induced carcinogensis by promoting apoptosis in cells treated with B[c]PhDE. We show that purified human MMR recognition proteins, MutS
and MutSß, specifically recognized B[c]PhDE-DNA adducts. Cell lines proficient in MMR exhibited several-fold more sensitivity to killing than cell lines defective in either MutS or MutL by B[c]PhDE; the nature of this sensitivity was shown to be due to increased apoptosis. Additionally, wild-type mice exposed to B[c]PhDE had intestinal crypt cells that underwent apoptosis significantly more often than intestinal crypt cells found in B[c]PhDE-treated Msh2–/– or Mlh1–/– mice. These findings, combined with previous studies, suggest that the MMR system may serve as a general sensor for chemical-caused DNA damage to prevent damaged cells from mutagenesis and carcinogenesis by promoting apoptosis.