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

Jianxin Wu, Bei Bei Zhu, Jin Yu, Hong Zhu, Lu Qiu, Mark S. Kindy, Liya Gu, Albrecht Seidel, Guo Min Li

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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, MutSα and MutSβ, 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 MutSα or MutLα 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.

Original languageEnglish (US)
Pages (from-to)6428-6434
Number of pages7
JournalNucleic acids research
Volume31
Issue number22
DOIs
StatePublished - Nov 15 2003

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ASJC Scopus subject areas

  • Genetics

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