Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adaptor Proteins, Signal Transducing
-
Adenosine Triphosphatases / genetics
-
Adenosine Triphosphatases / metabolism
-
Animals
-
Apoptosis / drug effects
-
Apoptosis / genetics
-
Bacterial Proteins / genetics
-
Bacterial Proteins / metabolism
-
Base Pair Mismatch
-
Carrier Proteins
-
Cell Line
-
Cell Line, Tumor
-
Cell Survival / drug effects
-
Cell Survival / genetics
-
DNA / chemistry*
-
DNA / drug effects
-
DNA / metabolism
-
DNA Adducts / chemistry*
-
DNA Adducts / metabolism
-
DNA Repair*
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
HeLa Cells
-
Humans
-
In Situ Nick-End Labeling
-
Intestine, Small / drug effects
-
Intestine, Small / metabolism
-
Intestine, Small / pathology
-
Mice
-
Mice, Knockout
-
MutL Protein Homolog 1
-
MutS DNA Mismatch-Binding Protein
-
MutS Homolog 2 Protein
-
Mutagens / chemistry*
-
Mutagens / pharmacology
-
Mutation
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism
-
Nuclear Proteins
-
Oligonucleotides / chemistry
-
Oligonucleotides / metabolism
-
Phenanthrenes / chemistry*
-
Phenanthrenes / pharmacology
-
Protein Binding
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism
Substances
-
Adaptor Proteins, Signal Transducing
-
Bacterial Proteins
-
Carrier Proteins
-
DNA Adducts
-
DNA-Binding Proteins
-
MLH1 protein, human
-
Mlh1 protein, mouse
-
Mutagens
-
Neoplasm Proteins
-
Nuclear Proteins
-
Oligonucleotides
-
Phenanthrenes
-
Proto-Oncogene Proteins
-
DNA
-
Adenosine Triphosphatases
-
MSH2 protein, human
-
Msh2 protein, mouse
-
MutL Protein Homolog 1
-
MutS DNA Mismatch-Binding Protein
-
MutS Homolog 2 Protein
-
benzo(c)phenanthrene