Epigenetic Silencing of the DNA Repair Enzyme

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 methyltransferaseexpressing 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 munit mKVA 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 ex pression 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 methyla tion in GM19S3(S) cells indicate the existence of signals that can induce widespread and abrupt alterations in cytosine methylation in human cells in culture.