DNA (cytosine-5)-methyltransferase 1, 3 alpha, and 3 beta (DNMT1/DNMT3A/DNMT3B)

DNA methyltransferases (DNMTs), specifically DNMT1, DNMT3A, and DNMT3B, are the primary enzymes responsible for establishing and maintaining DNA methylation patterns in the mammalian genome [2, 7]. DNMT1 serves as the maintenance methyltransferase, ensuring that epigenetic marks are faithfully copied onto newly synthesized DNA strands during replication, while DNMT3A and DNMT3B function as de novo methyltransferases that establish new methylation patterns during embryonic development and cellular differentiation [12, 14]. In many cancers, these enzymes are overexpressed or mutated, leading to the aberrant hypermethylation of tumor suppressor gene promoters, which silences their expression and promotes oncogenesis [8, 15]. Therapeutic targeting of DNMTs with hypomethylating agents, such as the FDA-approved nucleoside analogs azacitidine and decitabine, aims to reverse these epigenetic changes by trapping and degrading the enzymes, thereby reactivating silenced genes [1, 6]. While highly effective in treating hematological malignancies like myelodysplastic syndromes and acute myeloid leukemia, these drugs face challenges in solid tumors due to limited stability and systemic toxicities like myelosuppression [4, 9]. Beyond oncology, mutations in these enzymes are linked to rare developmental disorders, such as ICF syndrome, highlighting their critical role in genomic stability and human health [2, 10].

Other names

DNA methyltransferase familyDNMTsDNA (cytosine-5)-methyltransferase 1DNA (cytosine-5)-methyltransferase 3 alphaDNA (cytosine-5)-methyltransferase 3 betaMCMTDNMT3A2DNMT3B1

Nucleoside analogs (e.g., azacitidine, decitabine) are incorporated into DNA or RNA during replication and transcription, where they covalently trap DNA methyltransferase enzymes, leading to their proteasomal degradation and subsequent global DNA hypomethylation. Non-nucleoside inhibitors (e.g., RG108) act by binding directly to the enzyme's catalytic site or interfering with protein-protein interactions to inhibit methyltransferase activity without being incorporated into the genome.