Methylation of discrete regions of the O6-methylguanine DNA methyltransferase (MGMT) CpG island is associated with heterochromatinization of the MGMT transcription start site and silencing of the gene

George S. Watts, Russell O. Pieper, Joseph F. Costello, Yei Mei Peng, William S. Dalton, Bernard W. Futscher

Research output: Contribution to journalArticle

183 Scopus citations

Abstract

O6-Methylguanine DNA methyltransferase (MGMT) repairs the mutagenic and cytotoxic O6-alkylguanine lesions produced by environmental carcinogens and the chemotherapeutic nitrosoureas. As such, MGMT-mediated repair of O6- alkylguanine lesions constitutes a major form of resistance to nitrosourea chemotherapy and makes control of MGMT expression of clinical interest. The variability of expression in cell lines and tissues, along with the ease with which the MGMT phenotype reverts under various conditions, suggests that MGMT is under epigenetic control. One such epigenetic mechanism, 5-methylation of cytosines, has been linked to MGMT expression. We have used an isogenic human multiple myeloma tumor cell line model composed of an MGMT-positive parent cell line. RPMI g226/S, and its MGMT-negative variant termed 8226N, to study the control of MGMT expression. The loss of MGMT activity in 8226N was found to be due to the loss of detectable MGMT gene expression. Bisulfite sequencing of the MGMT CpG island promoter revealed large increases in the levels of CpG methylation within discrete regions of the 8226/V MGMT CpG island compared to those in 8226/S. These changes in CpG methylation are associated with local heterochromatinization of the 8226/V MGMT transcription start site and provide a likely mechanism for the loss of MGMT transcription in 8226/V.

Original languageEnglish (US)
Pages (from-to)5612-5619
Number of pages8
JournalMolecular and cellular biology
Volume17
Issue number9
DOIs
StatePublished - Sep 1997

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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