Human nuclear DNA polymerase (DNA Pol)

Human nuclear DNA polymerases are a specialized group of enzymes responsible for the synthesis of DNA molecules, playing a fundamental role in genome replication, maintenance, and repair (Burgers & Kunkel, 2017, PMID: 28301277). These enzymes are classified into four main families—A, B, X, and Y—each with distinct roles, such as the high-fidelity replication performed by Family B members (Pol alpha, delta, and epsilon) and the DNA repair functions of Family X (Pol beta) (Hubscher et al., 2002, PMID: 12036855). In the context of oncology, these polymerases are the primary targets for nucleoside analog drugs, which mimic natural nucleotides to inhibit DNA synthesis and induce apoptosis in rapidly dividing cancer cells (Galmarini et al., 2002, PMID: 12447602). Beyond their role as drug targets, specific mutations in the proofreading domains of POLE and POLD1 have emerged as vital biomarkers for identifying hypermutated tumors that are highly responsive to immunotherapy (Palles et al., 2013, PMID: 23263490). Consequently, these enzymes are central to both the mechanism of traditional cytotoxic therapies and the stratification of patients for modern precision medicine.

Other names

DNA-directed DNA polymeraseNuclear DNA polymeraseDNA nucleotidyltransferase (DNA-directed)Eukaryotic DNA polymerase

Inhibition of DNA synthesis through competitive binding with natural deoxyribonucleotide triphosphates (dNTPs) and subsequent incorporation into the nascent DNA strand, which results in DNA chain termination, stalling of replication forks, and the induction of DNA damage responses (StatPearls, 2023, NBK557680; Galmarini et al., 2002, PMID: 12447602).