DNA (cytosine-5)-methyltransferase 3 (DNMT3)

DNA (cytosine-5)-methyltransferase 3 (DNMT3) is a family of enzymes, primarily comprising DNMT3A and DNMT3B, responsible for establishing de novo DNA methylation patterns during embryonic development and cellular differentiation (UniProt Q9Y6K1, Q9UBC3). Unlike DNMT1, which maintains existing methylation patterns, DNMT3 enzymes add methyl groups to previously unmethylated CpG sites, playing a critical role in gene silencing, genomic imprinting, and X-chromosome inactivation (NIH, 2024). Dysregulation or mutation of DNMT3 members is frequently associated with various cancers, particularly hematologic malignancies like acute myeloid leukemia (AML), where mutations such as DNMT3A R882 lead to aberrant methylation and clonal expansion (PubMed, 2020). Therapeutic targeting of DNMT3 involves nucleoside analogs like azacitidine and decitabine, which induce global hypomethylation by trapping the enzyme on DNA, as well as emerging non-nucleoside inhibitors designed for greater specificity (MedChemExpress). However, challenges remain regarding the high toxicity and lack of selectivity of current inhibitors, which can lead to significant side effects like myelosuppression (Frontiers in Oncology, 2021).

Other names

DNA methyltransferase 3De novo DNA methyltransferaseDNMT3ADNMT3BDNMT3L

DNMT3 inhibitors primarily function by either incorporating into DNA as nucleoside analogs (e.g., azacitidine, decitabine) to covalently trap and degrade the enzyme, or by acting as non-nucleoside small molecules that competitively inhibit the catalytic site or disrupt protein-protein interactions, ultimately leading to DNA hypomethylation and reactivation of silenced genes.