MUTAGENICITY OF 5-AZA-2'-DEOXYCYTIDINE IS MEDIATED BY THE MAMMALIAN DNA METHYLTRANSFERASE

The cytosine analog 5-aza-2'-deoxycytidine has been used clinically to reactivate genes silenced by DNA methylation, In particular, patients with beta-thalassemia show fetal globin expression after administrati on of this hypomethylating drug, In addition, silencing of tumor suppr essor gene expression by aberrant DNA methylation in tumor cells may p otentially be reversed by a similar regimen, Consistent with its funct ion in maintaining tumor suppressor gene expression, 5-aza-2'-deoxycyt idine significantly reduces intestinal tumor multiplicity in the predi sposed Min mouse strain, Despite its utility as an anti-cancer agent, the drug is highly mutagenic by an unknown mechanism, To gain insight into how 5-aza-2'-deoxycytidine induces mutations in vivo, we examined the mutational spectrum in an Escherichia coil Inc I transgene in col onic DNA from 5-aza-2'-deoxycytidine-treated mice, Mutations induced b y 5-aza-2'-deoxycytidine were predominantly at CpG dinucleotides, whic h implicates DNA methyltransferase in the mutagenic mechanism, C:G-->G :C transversions were the predominant class of mutations observed, We suggest a model for how the mammalian DNA methyltransferase may be inv olved in facilitating these mutations, The observation that 5-aza-2'-d eoxycytidine-induced mutations are mediated by the enzyme suggests tha t novel inhibitors of DNA methyltransferase, which can inactivate the enzyme before its interaction with DNA, are needed for chemoprevention or long term therapy.