Mismatch repair processing of carcinogen-DNA adducts triggers apoptosis

Jianxin Wu, Liya Gu, Huixian Wang, Nicholas Geacintov, Guo M. Li

Research output: Contribution to journalArticle

Abstract

The DNA mismatch repair pathway is well known for its role in correcting biosynthetic errors of DNA replication. We report here a novel role for mismatch repair in signaling programmed cell death in response to DNA damage induced by chemical carcinogens. Cells proficient in mismatch repair were highly sensitive to the cytotoxic effects of chemical carcinogens, while cells defective in either human MutS or MutL homologs were relatively insensitive. Since wild-type cells but not mutant cells underwent apoptosis upon treatment with chemical carcinogens, the apoptotic response is dependent on a functional mismatch repair system. By analyzing p53 expression in several pairs of cell lines, we found that the mismatch repair-dependent apoptotic response was mediated through both p53-dependent and p53- independent pathways. In vitro biochemical studies demonstrated that the human mismatch recognition proteins hMutSα and hMutSβ efficiently recognized DNA damage induced by chemical carcinogens, suggesting a direct participation of mismatch repair proteins in mediating the apoptotic response. Taken together, these studies further elucidate the mechanism by which mismatch repair deficiency predisposes to cancer, i.e., the deficiency not only causes a failure to repair mismatches generated during DNA metabolism but also fails to direct damaged and mutation-prone cells to commit suicide.

Original languageEnglish (US)
Pages (from-to)8292-8301
Number of pages10
JournalMolecular and Cellular Biology
Volume19
Issue number12
StatePublished - Dec 1999

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DNA Mismatch Repair
DNA Adducts
Carcinogens
Apoptosis
DNA Damage
DNA Replication
Suicide
Proteins
Cell Death
Cell Line
Mutation
DNA

ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

Cite this

Mismatch repair processing of carcinogen-DNA adducts triggers apoptosis. / Wu, Jianxin; Gu, Liya; Wang, Huixian; Geacintov, Nicholas; Li, Guo M.

In: Molecular and Cellular Biology, Vol. 19, No. 12, 12.1999, p. 8292-8301.

Research output: Contribution to journalArticle

Wu, Jianxin ; Gu, Liya ; Wang, Huixian ; Geacintov, Nicholas ; Li, Guo M. / Mismatch repair processing of carcinogen-DNA adducts triggers apoptosis. In: Molecular and Cellular Biology. 1999 ; Vol. 19, No. 12. pp. 8292-8301.
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