In vitro and in vivo modulations of benzo[c]phenanthrene-DNA adducts by DNA mismatch repair system.

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.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Wu J,Zhu BB,Yu J,Zhu H,Qiu L,Kindy MS,Gu L,Seidel A,Li GM

doi

10.1093/nar/gkg875

keywords:

subject

Has Abstract

pub_date

2003-11-15 00:00:00

pages

6428-34

issue

22

eissn

0305-1048

issn

1362-4962

journal_volume

31

pub_type

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