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J Biol Chem, Vol. 274, Issue 28, 19538-19544, July 9, 1999

On the Substrate Specificity of DNA Methyltransferases
ADENINE-N⁶ DNA METHYLTRANSFERASES ALSO MODIFY CYTOSINE RESIDUES AT POSITION N⁴

From the Institut für Biochemie, Fachbereich Biologie, Heinrich-Buff-Ring 58, 35392 Giessen, Germany

Methylation of DNA is important in many organisms and essential in mammals. Nucleobases can be methylated at the adenine-N⁶, cytosine-N⁴, or cytosine-C⁵ atoms by specific DNA methyltransferases. We show here that the M.EcoRV, M.EcoRI, and Escherichia coli dam methyltransferases as well as the N- and C-terminal domains of the M.FokI enzyme, which were formerly all classified as adenine-N⁶ DNA methyltransferases, also methylate cytosine residues at position N⁴. Kinetic analyses demonstrate that the rate of methylation of cytosine residues by M.EcoRV and the M.FokI enzymes is reduced by only 1-2 orders of magnitude in relation to methylation of adenines. This result shows that although these enzymes methylate DNA in a sequence specific manner, they have a low substrate specificity with respect to the target base. This unexpected finding has implications on the mechanism of adenine-N⁶ DNA methyltransferases. Sequence comparisons suggest that adenine-N⁶ and cytosine-N⁴ methyltransferases have changed their reaction specificity at least twice during evolution, a model that becomes much more likely given the partial functional overlap of both enzyme types. In contrast, methylation of adenine residues by the cytosine-N⁴ methyltransferase M.BamHI was not detectable. On the basis of our results, we suggest that adenine-N⁶ and cytosine-N⁴ methyltransferases should be grouped into one enzyme family.

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