Generating mutations but providing chemosensitivity: The role of O 6-methylguanine DNA methyltransferase in human cancer

Manel Esteller, James G. Herman

Research output: Contribution to journalArticle

Abstract

O6-methylguanine DNA methyltransferase (MGMT) is a key enzyme in the DNA repair network. MGMT removes mutagenic and cytotoxic adducts from O6-guanine in DNA, the preferred point of attack of many carcinogens (i.e. methylnitrosourea) and alkylating chemotherapeutic agents (i.e. BCNU, temozolamide, etc.). Hypermethylation of the CpG island located in the promoter region of MGMT is primarily responsible for the loss of MGMT function in many tumor types. The methylation-mediated silencing of MGMT has two consequences for cancer. First, tumors with MGMT methylation have a new mutator phenotype characterized by the generation of transition point mutations in genes involved in cancer etiology, such as the tumor suppressor p53 and the oncogene K-ras. Second, MGMT hypermethylation demonstrates the possibility of pharmacoepigenomics: methylated tumors are more sensitive to the killing effects of alkylating drugs used in chemotherapy. These recent results underscore the importance of MGMT in basic and translational cancer research.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalOncogene
Volume23
Issue number1
DOIs
StatePublished - Jan 8 2004

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Keywords

  • Alkylating agents
  • CpG island hypermethylation
  • MGMT
  • O-methylguanine DNA methyltransferase
  • Transition mutations

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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