Methylation Inhibitors Can Increase the Rate of Cytosine Deamination by (Cytosine-5)-DNA Methyltransferase

摘要

The target cytosines of (cytosine-5)-DNA methyltransferases in prokaryotic and eukaryotic DNA show increased rates of C→T transition mutations compared to non-target cytosines. These mutations are induced either by the spontaneous deamination of 5-mC→T generating inefficiently repaired G:T rather than G:U mismatches, or by the enzyme-induced C→U deamination which occurs under conditions of reduced levels of S-adenosylmethionine (AdoMet) and S-adenosyl-homocysteine (AdoHcy). We tested whether various inhibitors of (cytosine-5)-DNA methyltransferases analogous to AdoMet and AdoHcy would affect the rate of enzyme-induced deamination of the target cytosine by M.HpaII and M.SssI. Interestingly, we found two compounds, sinefungin and 5′-amino-5′-deoxyadenosine, that increased the rate of deamination 103-fold in the presence and 104-fold in the absence of AdoMet and AdoHcy. We have therefore identified the first mutagenic compounds specific for the target sites of (cytosine-5)-DNA methyltransferases. A number of analogs of AdoMet and AdoHcy have been considered as possible antiviral, anticancer, antifungal and anti-parasitic agents. Our findings show that chemotherapeutic agents with affinities to the cofactor binding pocket of (cytosine-5)-DNA methyltransferase should be tested for their potential mutagenic effects.