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Epigenetic Silencing of the DNA Repair Enzyme O⁶-Methylguanine-DNA Methyltransferase in Mex^- Human Cells

Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Hertfordshire EN6 3LD, England

Regulation of the expression of the DNA repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT) has been investigated in a number of human lymphoblastoid cell lines. In a number of Mex^- cell lines that do not express methyltransferase activity, CpG sequences in the mgmt gene were hypomethylated with respect to methyltransferase-expressing Mex⁺ lines. In the cell line GM1953(S), in which the mgmt gene is coregulated with the thymidine kinase and galactokinase genes, reexpression of all three activities was experimentally induced. In this case, the mgmt gene in the nonexpressing cells was found to be hypermethylated and underwent a demethylation at CpG sequences that was coincident with the reappearence of the mgmt mRNA and the three enzyme activities. The simultaneous silencing of three activities in these cells was correlated with an increase in DNA 5-methylcytosine that was widespread thoughout the genome. The data indicate that MGMT expression can be controlled epigenetically in human lymphoid cell lines, although the relationship between cytosine methylation and MGMT expression is complex. Furthermore, the rapid alterations in methylation in GM1953(S) cells indicate the existence of signals that can induce widespread and abrupt alterations in cytosine methylation in human cells in culture.

¹ To whom requests for reprints should be addressed.

Received 3/18/92. Accepted 7/22/92.

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