Nucleic Acids Research, Vol 24, Issue 16 3267-3275, Copyright © 1996 by Oxford University Press
JM Zingg, JC Shen, AS Yang, H Rapoport and PA Jones
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.
ARTICLES
Methylation inhibitors can increase the rate of cytosine deamination by (cytosine-5)-DNA methyltransferase
Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles 90033, USA.
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