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Coregulation of the Human O⁶-Methylguanine-DNA Methyltransferase with Two Unrelated Genes That Are Closely Linked¹

Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Herts., EN6 3LD United Kingdom [P. K., C. S., P. M., S. C-S.], and MRC Cell Mutation Unit, University of Sussex, Falmer, Brighton, BN1 9RR United Kingdom [A. P.]

The loss of expression of the enzyme O⁶-methylguanine-DNA methyltransferase (the Mex^- phenotype), which often results from cellular transformation, confers hypersensitivity to alkylating agents. We have observed two unrelated examples in which human cell lines have undergone a spontaneous alteration in their Mex phenotype during propagation in vitro. The change was reversible and was not the result of mutation. In both cases a loss of methyltransferase expression was accompanied by a simultaneous loss of expression of two metabolically unrelated enzymes: thymidine kinase and galactokinase. "Reversion" to methyl-transferase expression was accompanied by simultaneous reexpression of both kinase activities. A third example of this coordinate gene regulation was seen with the Burkitt's lymphoma cell line Raji which expresses methyltransferase, thymidine kinase, and galactokinase at high levels. A thymidine kinase^- Raji cell line derived by bromodeoxyuridine mutagenesis that is also Mex^- was found to be galactokinase^-. It appears that methyltransferase expression may in some instances be coordinately regulated with the tk and glk loci which are closely linked on human chromosome 17.

¹ This work was supported by the Imperial Cancer Research Fund and by European Communities Contract B16-0142-UK(H) to the MRC Cell Mutation Unit.

² To whom requests for reprints should be addressed.

Received 8/17/89. Revised 11/20/89. Accepted 11/28/89.