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Selective Depletion of Human DNA-Methyltransferase DNMT1 Proteins by Sulfonate-derived Methylating Agents¹

Chemical Carcinogenesis Laboratory, Institute of Molecular and Cell Biology [L. S-H. C., E. H-H. T., H-K. O., B. F-L. L.], Department of Physiology, Faculty of Medicine [B. F-L. L.], National University of Singapore, Singapore 117609, Republic of Singapore

5-Methylcytosine residues in the DNA (DNA methylation) are formed fromthe transfer of the methyl group from S-adenosylmethionine to the C-5 position of cytosine by the DNA-(cytosine-5) methyltransferases (DNMTs). Although regional hypermethylation and global hypomethylation of the genome are commonly observed in neoplastic cells, how these aberrant methylation patterns occur remains unestablished. We report here that sulfonate-derived methylating agents, unlike N-methylnitrosourea or iodomethane, are potent in depleting DNMT1 proteins in human cells, in addition to their DNA-damaging properties. Their effects on cellular DNMT1 are time and dosage dependent but independent of cell type. Unlike -irradiation, these agents apparently do not activate the p53/p21^WAF1 DNA damage response pathway to deplete the DNMT1 proteins because cells with wild-type, mutated, or inactivated p53 behave similarly. However, cell cycle analysis and protease assay studies strongly suggest that methylmethanesulfonate may activate a cellular protease to degrade DNMT1. These results explain why reported observations on the effect of alkylating agents on DNMT1 activities in human cells vary significantly and provide a crucial link to understand the mechanism behind genomic hypomethylation.

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