DNMT1 (DNA methyltransferase 1)

Class

Hypomethylating agent (pyrimidine nucleoside analog)

Pathway

DNA methylation / epigenetic reactivation of silenced tumor-suppressor genes

DNMT1 (DNA methyltransferase 1) is the principal enzyme that maintains DNA methylation patterns as cells divide, copying methylation marks from the parent DNA strand onto the newly synthesized strand. Methylation of cytosine bases, particularly at gene-regulatory regions called CpG islands, is a normal mechanism for keeping genes switched off. In many cancers, tumor-suppressor genes become abnormally methylated and silenced, allowing malignant cells to bypass growth controls. Hypomethylating agents are nucleoside analogs that are incorporated into DNA in place of cytidine during replication; once incorporated, they trap DNMT1 and cause its degradation, progressively reducing overall methylation. As methylation is lost over successive cell divisions, previously silenced genes—including tumor suppressors and genes involved in immune recognition—can become reactivated, potentially restoring normal regulatory control or making malignant cells more susceptible to differentiation or immune clearance. This mechanism is broadly relevant in hematologic malignancies, such as myelodysplastic disorders and acute myeloid leukemia, where abnormal methylation patterns are a recognized disease driver, and it represents a distinct strategy from direct cytotoxic chemotherapy, working instead by reprogramming gene expression rather than solely by killing dividing cells outright.