DNA methyltransferase 1 (DNMT1) and DNA methyltransferase 3 alpha (DNMT3A) (DNMT1/3A)

DNA methyltransferase 1 (DNMT1) and DNA methyltransferase 3 alpha (DNMT3A) are essential enzymes that regulate the epigenetic landscape of the genome by catalyzing the transfer of methyl groups to cytosine residues in DNA [1.1.1, 1.4.1]. DNMT1 is primarily responsible for maintaining existing methylation patterns during DNA replication, while DNMT3A establishes new (de novo) methylation patterns during development and differentiation [1.2.1, 1.4.3]. In many cancers, particularly hematologic malignancies like acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), these enzymes are frequently overexpressed or mutated, leading to the silencing of tumor suppressor genes through promoter hypermethylation [1.1.1, 1.2.2]. Therapeutic strategies targeting these enzymes utilize hypomethylating agents like azacitidine and decitabine, which act as nucleoside analogs that irreversibly bind and inhibit DNMTs, thereby restoring normal gene expression [1.2.3, 1.2.5]. Beyond oncology, mutations in DNMT1 and DNMT3A are linked to neurodegenerative and developmental disorders, such as hereditary sensory autonomic neuropathy type 1E (HSAN1E) and overgrowth syndromes, highlighting their critical role in cellular homeostasis [1.1.2, 1.1.4].

Other names

DNMT1DNMT3ADNA MTaseMCMTDNA methyltransferase 3ATBRSDNMT3A2DNA (cytosine-5)-methyltransferase 1DNA (cytosine-5)-methyltransferase 3 alpha

Inhibition of DNA methyltransferase activity through covalent trapping of the enzymes on DNA (suicide substrate mechanism), leading to proteasomal degradation of DNMTs, global DNA hypomethylation, and the reactivation of silenced tumor suppressor genes [1.2.2, 1.2.3].