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

DNA methyltransferases (DNMTs), specifically DNMT1, DNMT3A, and DNMT3B, are the primary enzymes responsible for the establishment and maintenance of DNA methylation patterns in mammals [1.1.1, 1.4.1]. DNMT1 is the most abundant member and acts as a maintenance methyltransferase, ensuring the faithful inheritance of methylation marks during DNA replication by targeting hemimethylated CpG sites [1.1.2, 1.4.5]. DNMT3A and DNMT3B are de novo methyltransferases that establish new methylation patterns during embryonic development and cellular differentiation [1.2.2, 1.4.4]. These enzymes are critical for gene silencing, genomic imprinting, and X-chromosome inactivation, and their dysregulation is a hallmark of cancer, where promoter hypermethylation leads to the silencing of tumor suppressor genes [1.2.1, 1.3.4]. DNMTs are major therapeutic targets in hematological malignancies, with FDA-approved inhibitors like azacitidine and decitabine functioning as suicide substrates that trap the enzymes on DNA, leading to their degradation and the reversal of epigenetic silencing [1.1.4, 1.3.5]. Beyond cancer, mutations in these enzymes are linked to developmental disorders such as ICF syndrome (DNMT3B) and various neurodevelopmental conditions [1.2.2, 1.2.5]. Therapeutic challenges include the lack of isoform specificity and the potential for systemic toxicity, such as myelosuppression, due to the global nature of DNA hypomethylation [1.3.1, 1.3.4]. Current research focuses on developing non-nucleoside inhibitors and improving the delivery of existing agents to solid tumors [1.2.3, 1.3.4].

Other names

DNA methyltransferase 1DNA methyltransferase 3ADNA methyltransferase 3BDNMT1DNMT3ADNMT3BMCMTDNA (cytosine-5)-methyltransferase 3 alphaDNA (cytosine-5)-methyltransferase 3 betaHsaIIIB

DNMT inhibitors, primarily nucleoside analogs like azacitidine and decitabine, are incorporated into DNA (or RNA for azacitidine) during the S-phase of the cell cycle. Once incorporated, they form a covalent bond with the catalytic cysteine residue of DNMT enzymes (DNMT1, DNMT3A, and DNMT3B) during the methylation reaction, effectively trapping the enzymes on the DNA. This leads to the depletion of active DNMTs, subsequent proteasomal degradation of the trapped enzymes, and a global loss of DNA methylation (hypomethylation) in daughter cells. This hypomethylation results in the reactivation of previously silenced tumor suppressor genes and the induction of cell differentiation or apoptosis [1.1.4, 1.3.2, 1.3.5].