DNA containing incorporated 5-aza-2′-deoxycytidine residues (5-aza-dC-DNA)

DNA containing incorporated 5-aza-2′-deoxycytidine residues is a modified genomic structure that serves as the functional mediator for the therapeutic effects of decitabine [PubChem, CID 451669]. This entity is created when the cytidine analog decitabine is phosphorylated into 5-aza-2′-deoxycytidine triphosphate and subsequently incorporated into the DNA of dividing cells during the S-phase [StatPearls, NBK537125]. The substitution of a nitrogen atom at the 5-position of the pyrimidine ring, instead of the carbon found in natural cytosine, prevents the resolution of the covalent intermediate formed during DNA methylation [JBC, 2012]. As a result, DNA methyltransferases (DNMTs), particularly DNMT1, become irreversibly trapped on the DNA strand, leading to their proteasomal degradation [Nature Reviews Drug Discovery, 2012]. This depletion of DNMTs causes global DNA hypomethylation, which allows for the reactivation of tumor suppressor genes that were previously silenced by hypermethylation [NIH, NCI Thesaurus]. This molecular mechanism is primarily utilized in the treatment of hematologic malignancies, including myelodysplastic syndromes and acute myeloid leukemia, to induce cell differentiation and apoptosis [FDA, Dacogen Label].

Other names

Decitabine-DNA adduct5-aza-2'-deoxycytidine-DNAAza-DNADecitabine-incorporated DNA5-aza-dC-modified DNA

Covalent trapping and suicide inhibition of DNA methyltransferases (DNMT1, DNMT3A, DNMT3B) following incorporation into the DNA strand during replication [StatPearls, NBK537125].