DNA-directed DNA polymerase (DNA Pol) (DNA Pol)

DNA-directed DNA polymerase is a fundamental enzyme family responsible for the synthesis of DNA molecules from nucleoside triphosphates, playing a central role in DNA replication and repair (UniProt, 2023). In clinical oncology, specific isoforms such as DNA polymerase alpha, delta, and epsilon are the primary targets for the antimetabolite drug cytarabine (Ara-C) (StatPearls, 2023). Cytarabine functions as a prodrug that must be intracellularly converted into its active form, cytarabine triphosphate (ara-CTP), by the enzyme deoxycytidine kinase (dCK) (DrugBank, 2023). Ara-CTP acts as a competitive inhibitor of DNA polymerase by mimicking the natural substrate deoxycytidine triphosphate (dCTP). Once DNA polymerase incorporates ara-CTP into the nascent DNA strand, it causes stalling of the replication fork and prevents further chain elongation, a process known as chain termination (PubMed, 2022). This disruption of DNA synthesis triggers S-phase cell cycle arrest and leads to programmed cell death (apoptosis), making it highly effective against rapidly proliferating malignant cells in diseases like acute myeloid leukemia (AML) and non-Hodgkin lymphoma (NIH, 2023).

Other names

DNA polymeraseDNA-directed DNA polymeraseDNA polymerase alphaDNA polymerase deltaDNA polymerase epsilonPOLA1POLD1POLE

Competitive inhibition of DNA polymerase by the active metabolite cytarabine triphosphate (ara-CTP), which competes with dCTP for incorporation into DNA, leading to chain termination and inhibition of DNA synthesis (StatPearls, 2023; PubChem, 2023).