DNA polymerase (nuclear) (DNA Pol) (DNA Pol)

DNA polymerases involved in nuclear DNA synthesis are a group of essential enzymes responsible for the high-fidelity replication and repair of the nuclear genome (UniProt: P15884, P28908). The primary replicative enzymes include Polymerase alpha (Pol α), which initiates synthesis, and Polymerases delta (Pol δ) and epsilon (Pol ε), which catalyze the elongation of the lagging and leading strands, respectively (Nature Reviews Cancer, 2016). These enzymes utilize deoxyribonucleotide triphosphates (dNTPs) to synthesize DNA strands complementary to a template, ensuring the accurate transmission of genetic information during the S-phase of the cell cycle. In oncology, these polymerases are significant therapeutic targets for antimetabolite drugs, such as Cytarabine and Gemcitabine, which act as nucleoside analogs to inhibit polymerase activity or cause lethal chain termination in rapidly dividing malignant cells (StatPearls, 2023). Beyond replication, nuclear polymerases like Pol beta (Pol β) are critical for DNA repair pathways, such as base excision repair, which maintain genomic stability. Mutations in the proofreading domains of Pol δ and Pol ε are associated with hypermutated tumor phenotypes and hereditary cancer syndromes, making them important diagnostic and prognostic markers (PubMed: PMC4351158). Therapeutic challenges include the lack of specificity for cancerous versus healthy dividing cells, leading to significant side effects like myelosuppression.

Other names

DNA-directed DNA polymeraseNuclear DNA polymeraseReplicative DNA polymeraseDNA nucleotidyltransferaseDNA polymerase alphaDNA polymerase deltaDNA polymerase epsilon

Inhibition of DNA synthesis through competitive antagonism of natural deoxyribonucleotide triphosphates (dNTPs) and induction of DNA chain termination following incorporation into the nascent DNA strand.