DNA (cytosine-5)-methyltransferase 1, 3A, and 3B (DNMT1/3A/3B)

DNA (cytosine-5)-methyltransferase 1 (DNMT1), 3A (DNMT3A), and 3B (DNMT3B) are the primary enzymes responsible for establishing and maintaining DNA methylation patterns in the mammalian genome [1, 2]. DNMT1 functions as the maintenance methyltransferase that copies methylation patterns during DNA replication, while DNMT3A and DNMT3B are de novo methyltransferases that establish new marks during development and differentiation [5, 12]. These enzymes catalyze the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to cytosine residues, primarily at CpG sites, leading to gene silencing and chromatin stabilization [6, 10]. In many cancers, particularly myeloid malignancies, these enzymes are overexpressed or mutated, causing aberrant hypermethylation of tumor suppressor genes [4, 13]. Therapeutic targeting of these DNMTs with hypomethylating agents like azacitidine and decitabine is a standard clinical approach to restore gene expression and induce cell differentiation [4, 6]. However, these treatments are often associated with significant safety concerns, including myelosuppression and potential genomic instability due to global hypomethylation [4, 17].

Other names

DNA methyltransferase 1DNA methyltransferase 3ADNA methyltransferase 3BDNMT1DNMT3ADNMT3BCytosine-5 methyltransferasesMCMTCXXC9HSN1EICFICF1

Nucleoside analogs (e.g., azacitidine, decitabine) are incorporated into DNA during the S-phase of the cell cycle, where they covalently trap DNA methyltransferase enzymes. This irreversible binding leads to the depletion of active DNMTs, resulting in global DNA hypomethylation and the reactivation of silenced tumor suppressor genes. Non-nucleoside inhibitors may act by competing with the substrate or the methyl donor (SAM) at the catalytic site.