In vitro and in vivo modulations of benzo[c]phenanthrene-DNA adducts by DNA mismatch repair system.
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(alpha) and MutSbeta, 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(alpha) or MutL(alpha) 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.
Wu
Jianxin
J
Markey Cancer Center and Department of Pathology, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
Zhu
Bei-Bei
BB
Yu
Jin
J
Zhu
Hong
H
Qiu
Lu
L
Kindy
Mark S
MS
Gu
Liya
L
Seidel
Albrecht
A
Li
Guo-Min
GM
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000070957:MutL Protein Homolog 1; D051719:MutS DNA Mismatch-Binding Protein; D051718:MutS Homolog 2 Protein; D009153:Mutagens / Q000737:chemistry* / Q000494:pharmacology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism; D010616:Phenanthrenes / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D001426:Bacterial Proteins; D002352:Carrier Proteins; D018736:DNA Adducts; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C501485:Mlh1 protein, mouse; D009153:Mutagens; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D009841:Oligonucleotides; D010616:Phenanthrenes; D011518:Proto-Oncogene Proteins; D004247:DNA; D000251:Adenosine Triphosphatases; C497172:MSH2 protein, human; C497173:Msh2 protein, mouse; D000070957:MutL Protein Homolog 1; D051719:MutS DNA Mismatch-Binding Protein; D051718:MutS Homolog 2 Protein; C002615:benzo(c)phenanthrene