Role of DNA mismatch repair in apoptotic responses to therapeutic agents

Mark Meyers, Arlene Hwang, Mark W. Wagner, David A. Boothman

Research output: Contribution to journalReview article

48 Scopus citations

Abstract

Deficiencies in DNA mismatch repair (MMR) have been found in both hereditary cancer (i.e., hereditary nonpolyposis colorectal cancer) and sporadic cancers of various tissues. In addition to its primary roles in the correction of DNA replication errors and suppression of recombination, research in the last 10 years has shown that MMR is involved in many other processes, such as interaction with other DNA repair pathways, cell cycle checkpoint regulation, and apoptosis. Indeed, a cell's MMR status can influence its response to a wide variety of chemotherapeutic agents, such as temozolomide (and many other methylating agents), 6-thioguanine, cisplatin, ionizing radiation, etoposide, and -5-fluorouracil. For this reason, identification of a tumor's MMR deficiency (as indicated by the presence of microsatellite instability) is being utilized more and more as a prognostic indicator in the clinic. Here, we describe the basic mechanisms of MMR and apoptosis and investigate the literature examining the influence of MMR status on the apoptotic response following treatment with various therapeutic agents. Furthermore, using isogenic MMR-deficient (HCT116) and MMR-proficient (HCT116 3-6) cells, we demonstrate that there is no enhanced apoptosis in MMR-proficient cells following treatment with 5-fluoro2′- deoxyuridine. In fact, apoptosis accounts for only a small portion of the induced cell death response.

Original languageEnglish (US)
Pages (from-to)249-264
Number of pages16
JournalEnvironmental and Molecular Mutagenesis
Volume44
Issue number4
DOIs
StatePublished - Nov 12 2004

Keywords

  • Alkylating agents
  • Apoptosis
  • DNA mismatch repair
  • Fluoropyrimidines
  • P53

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)
  • Health, Toxicology and Mutagenesis

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