DNA (cytosine-5)-methyltransferase (DNMT) (DNMT)

DNA (cytosine-5)-methyltransferases (DNMTs), including the primary isoforms DNMT1, DNMT3A, and DNMT3B, are enzymes responsible for the epigenetic modification of DNA by transferring a methyl group to the C5 position of cytosine residues (UniProt Consortium, 2023). DNMT1 maintains established methylation patterns during DNA replication, while DNMT3A and DNMT3B are responsible for de novo methylation during development and cellular differentiation (Lyko, 2018). These enzymes are critical for regulating gene expression, maintaining genomic stability, and managing processes like X-chromosome inactivation and genomic imprinting (PubMed, 2022). In many cancers, particularly hematologic malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), DNMTs are often dysregulated, leading to the hypermethylation and silencing of tumor suppressor genes (Ley et al., 2013). Azacitidine is a chemical analog of cytidine that acts as a potent inhibitor of these enzymes; upon incorporation into DNA, it irreversibly binds to DNMTs, causing their degradation (StatPearls, 2023). This mechanism results in global DNA hypomethylation, which can restore the expression of silenced genes and promote the differentiation or death of malignant cells (PubChem, 2024). While effective, targeting DNMTs with azacitidine is associated with significant clinical challenges, most notably severe myelosuppression and gastrointestinal toxicity (FDA Label, Vidaza). Understanding the specific roles of DNMT isoforms continues to be a focus for developing more selective epigenetic therapies in oncology.

Other names

DNMT1DNMT3ADNMT3BDNA methyltransferaseCytosine-5-methyltransferaseMCMT

Azacitidine is a nucleoside analog that incorporates into DNA and RNA; in DNA, it forms a covalent complex with DNA methyltransferases (DNMTs), leading to enzyme depletion, DNA hypomethylation, and reactivation of silenced tumor suppressor genes (StatPearls, 2023; PubChem, 2024).