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On the Substrate Specificity of DNA Methyltransferases

A. Jeltsch,F. Christ,M. Fatemi,M. Roth

Published 1999 in Journal of Biological Chemistry

ABSTRACT

Methylation of DNA is important in many organisms and essential in mammals. Nucleobases can be methylated at the adenine-N 6, cytosine-N 4, or cytosine-C 5 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-N 6 DNA methyltransferases, also methylate cytosine residues at position N 4. 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-N 6 DNA methyltransferases. Sequence comparisons suggest that adenine-N 6 and cytosine-N 4 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-N 4 methyltransferase M.BamHI was not detectable. On the basis of our results, we suggest that adenine-N 6 and cytosine-N 4 methyltransferases should be grouped into one enzyme family.

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