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J. Biol. Chem., Vol. 278, Issue 23, 20812-20820, June 6, 2003

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The Methyl Donor S-Adenosylmethionine Inhibits Active Demethylation of DNA

A CANDIDATE NOVEL MECHANISM FOR THE PHARMACOLOGICAL EFFECTS OF S-ADENOSYLMETHIONINE^*

Nancy Detich   ¶, Stefan Hamm  ||, George Just ** , J. David Knox  and Moshe Szyf  

From the Departments of Pharmacology and Therapeutics and ^**Chemistry, McGill University, Montreal, Quebec H3G 1YG, Canada

S-Adenosylmethionine (AdoMet) is the methyl donor of numerous methylation reactions. The current model is that an increased concentration of AdoMet stimulates DNA methyltransferase reactions, triggering hypermethylation and protecting the genome against global hypomethylation, a hallmark of cancer. Using an assay of active demethylation in HEK 293 cells, we show that AdoMet inhibits active demethylation and expression of an ectopically methylated CMV-GFP (green fluorescent protein) plasmid in a dose-dependent manner. The inhibition of GFP expression is specific to methylated GFP; AdoMet does not inhibit an identical but unmethylated CMV-GFP plasmid. S-Adenosylhomocysteine (AdoHcy), the product of methyltransferase reactions utilizing AdoMet does not inhibit demethylation or expression of CMV-GFP. In vitro, AdoMet but not AdoHcy inhibits methylated DNA-binding protein 2/DNA demethylase as well as endogenous demethylase activity extracted from HEK 293, suggesting that AdoMet directly inhibits demethylase activity, and that the methyl residue on AdoMet is required for its interaction with demethylase. Taken together, our data support an alternative mechanism of action for AdoMet as an inhibitor of intracellular demethylase activity, which results in hypermethylation of DNA.

Received for publication, November 20, 2002 , and in revised form, March 25, 2003.

^* This work was supported in part by the National Cancer Institute of Canada and Natural Science and Engineering Research Council Canada. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to the results of this work.

^¶ Recipient of the Canadian Institute of Health Research Doctoral Fellowship and the McGill Faculty of Medicine Internal Fellowship.

^|| Supported by postdoctoral research stipend from Deutsche Forschungsgemeinschaft.

Supported by Grant 228183 from the Natural Science and Engineering Research Council.

To whom correspondence should be addressed: 3655 Sir William Osler Promenade, Montreal, Quebec H3G 1Y6, Canada. Tel.: 514-398-7107; Fax: 514-398-6690; E-mail: mszyf{at}pharma.mcgill.ca.

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