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

Research output: Contribution to journalArticle

14 Citations (Scopus)

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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DNA Mismatch Repair
DNA Adducts
Apoptosis
Carcinogenesis
Environmental Carcinogens
Cell Line
Epoxy Compounds
Adenine
benzo(c)phenanthrene
1,2-epoxy-3,4-dihydroxy-1,2,3,4-tetrahydrobenzo(c)phenanthrene
In Vitro Techniques
Mutagenesis
DNA Damage
Maintenance
Genome
DNA

ASJC Scopus subject areas

  • Genetics

Cite this

In vitro and in vivo modulations of benzo[c]phenanthrene-DNA adducts by DNA mismatch repair system. / Wu, Jianxin; Zhu, Bei Bei; Yu, Jin; Zhu, Hong; Qiu, Lu; Kindy, Mark S.; Gu, Liya; Seidel, Albrecht; Li, Guo Min.

In: Nucleic Acids Research, Vol. 31, No. 22, 15.11.2003, p. 6428-6434.

Research output: Contribution to journalArticle

Wu, Jianxin ; Zhu, Bei Bei ; Yu, Jin ; Zhu, Hong ; Qiu, Lu ; Kindy, Mark S. ; Gu, Liya ; Seidel, Albrecht ; Li, Guo Min. / In vitro and in vivo modulations of benzo[c]phenanthrene-DNA adducts by DNA mismatch repair system. In: Nucleic Acids Research. 2003 ; Vol. 31, No. 22. pp. 6428-6434.
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