Mechanism of inhibition of DNA methyltransferase by 5-azacytosine substituted DNA

Abstract

There are two lines of evidence indicating that enzymatic methylation of cytosine residues in DNA may influence the expression of genes in vertebrate cells. First, a general correlation exists between the persistance of unmodified methylation sites in or near coding sequences of specific genes and the expression of these genes. Such sites are methylated in DNA of cells where the genes are inactive and lack methyl groups in cells where the genes are expressed. (For recent reviews see Razin and Riggs, 1980; Ehrlich and Wang, 1981.) Second, at least two agents which inhibit methylation of cytosine residues in DNA, L-ethionine (Christman, et al, 1977) and 5-azacytidine (Jones and Taylor, 1980), are able to induce stable alterations of gene expression in mammalian cells. 5-azacytidine (5-aza-CR) is of particular interest in this respect because it is not a general inhibitor of transmethylation reactions but instead specifically inhibits methylation of cytosine residues in DNA and RNA (Friedman, 1979; Lu and Randerath, 1978).