Methylation inhibitors can increase the rate of cytosine deamination by (cytosine-5)-DNA methyltransferase.
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-adenosylhomocysteine (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 10(3)-fold in the presence and 10(4)-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 antiparasitic 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.
Zingg
J M
JM
Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles 90033, USA.
Shen
J C
JC
Yang
A S
AS
Rapoport
H
H
Jones
P A
PA
D001419:Bacteria / Q000201:enzymology; D001667:Binding, Competitive; D004247:DNA / Q000378:metabolism; D015257:DNA-Cytosine Methylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003641:Deamination; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008745:Methylation; D011485:Protein Binding; D012435:S-Adenosylhomocysteine / Q000031:analogs & derivatives*; D012436:S-Adenosylmethionine / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D012436:S-Adenosylmethionine; D004247:DNA; D012435:S-Adenosylhomocysteine; C029641:DNA modification methylase HpaII; C081573:DNA modification methylase SssI; D015257:DNA-Cytosine Methylases