Figure 2.

Inhibition of DNMTs upon incorporation of decitabine and azacytidine into DNA. The genomic DNA methylation landscape consists of methylated and unmethylated cytosines. Upon multiple phosphorylation steps by DCK (deoxycytidine kinase), NMPK (nucleoside monophosphate kinases) and NDPK (nucleoside diphosphatase kinase), decitabine becomes 5-aza-dCTP, which gets incorporated into DNA. Upon phosphorylation steps by UCK (uridine cytidine kinase) and NMPK (nucleoside monophosphate kinases), azacytidine is converted into 5-aza-CDP, which is recognized by ribonucleotide reductase (RNR) leading to the formation of 5-aza-dCDP. This reactive analog is further phosphorylated to 5-aza-dCTP by NDPK (nucleoside diphosphatase kinase), which is then integrated into genomic DNA. Upon DNA replication, DNMT1 maintains the methylation status of the genome. However, DNMT1 becomes covalently bound to the cytosine analog, 5-aza-dCTP, which prevents DNMT1 activity leading to genomic hypomethylation and loss of epigenetic memory. Additionally, other DNMT enzymes, DNMT3a and DNMT3b, can also form an irreversible interaction with azanucleosides leading to hypomethylation of the genome. Collectively, this drug-mediated DNA hypomethylation causes anti-tumorigenic effects including inhibition of the cell cycle, DNA repair impairments, activation of pro-apoptotic and tumor suppressor genes.