DNA methyltransferase 3 (DNMT3)

DNA methyltransferase 3 (DNMT3) is a family of enzymes, primarily comprising DNMT3A and DNMT3B, that are responsible for the de novo establishment of DNA methylation patterns during embryonic development and cellular differentiation (PubMed:12138111, PubMed:16357870). These enzymes catalyze the transfer of a methyl group from S-adenosyl-L-methionine to the C5 position of cytosine residues, typically within CpG dinucleotides, which serves as a critical epigenetic mechanism for gene silencing, genomic imprinting, and the maintenance of chromosomal stability (PubMed:30478443). Dysregulation of DNMT3 activity, through either somatic mutations or overexpression, is a significant driver in various malignancies, most notably acute myeloid leukemia (AML), where DNMT3A mutations are among the most frequent genetic alterations (PubMed:29414941). Additionally, germline mutations in DNMT3 members are linked to developmental disorders such as Tatton-Brown-Rahman syndrome and ICF syndrome (PubMed:27153398). Therapeutic strategies targeting DNMT3 primarily utilize hypomethylating agents like azacitidine and decitabine, which are nucleoside analogs that incorporate into DNA and irreversibly trap the enzymes, leading to their degradation and the subsequent reactivation of silenced tumor suppressor genes.

Other names

De novo DNA methyltransferaseDNMT3 familyDNA (cytosine-5)-methyltransferase 3DNA methyltransferase 3 alpha (DNMT3A)DNA methyltransferase 3 beta (DNMT3B)DNA methyltransferase 3-like (DNMT3L)

Covalent inhibition via DNA incorporation (nucleoside analogs); non-covalent binding to the catalytic site (non-nucleoside inhibitors); induction of proteasomal degradation of the enzyme.