Host nuclear DNA polymerase (DNA Pol)

Host nuclear DNA polymerases are a specialized group of enzymes responsible for the high-fidelity synthesis of DNA within the eukaryotic nucleus. The primary polymerases involved in genomic replication are DNA polymerase alpha (Pol α), delta (Pol δ), and epsilon (Pol ε), which work coordinately to synthesize the leading and lagging strands (UniProt: P09884, P28907). Other nuclear polymerases, such as Pol beta (Pol β), play essential roles in DNA repair pathways like base excision repair to maintain genomic integrity (PubMed: 25403441). In oncology, these enzymes are critical therapeutic targets because malignant cells require rapid DNA synthesis to support uncontrolled proliferation. Antimetabolite drugs, including cytarabine and gemcitabine, act as nucleoside analogs that are phosphorylated intracellularly and subsequently inhibit polymerase activity or cause premature DNA chain termination (StatPearls: NBK554540). While effective against cancer, the inhibition of host DNA polymerases also affects rapidly dividing healthy cells, leading to significant clinical toxicities such as bone marrow suppression and mucosal damage. Furthermore, mutations in the proofreading domains of Pol δ and Pol ε are recognized as important biomarkers for hypermutated phenotypes in colorectal and endometrial cancers, often predicting favorable responses to immunotherapy (PubMed: 30633911).

Other names

DNA-directed DNA polymeraseDNA nucleotidyltransferase (DNA-directed)Nuclear DNA polymeraseEukaryotic DNA polymerase

Competitive inhibition of deoxyribonucleotide triphosphate (dNTP) binding and incorporation into the nascent DNA strand, often resulting in DNA chain termination or replication fork arrest.