DNA polymerase alpha and related replicative DNA polymerases (Pol alpha/delta/epsilon)

DNA polymerase alpha, delta, and epsilon are the essential enzymes responsible for the replication of the eukaryotic nuclear genome (UniProt P09884, P28340, Q9Y5S4). DNA polymerase alpha, in complex with primase, initiates DNA synthesis by creating short RNA-DNA primers, which are then extended by DNA polymerase epsilon on the leading strand and DNA polymerase delta on the lagging strand (Wikipedia: DNA polymerase). These enzymes are members of the Family B DNA polymerases and are characterized by high fidelity and processivity, often requiring the sliding clamp PCNA for efficient synthesis (NIH: PMC2519115). Beyond their roles in replication, they are integral to various DNA repair pathways, such as nucleotide excision repair and base excision repair (PubMed: 22119860). Due to their essential role in cell proliferation, they are significant therapeutic targets in oncology and virology; for instance, nucleoside analogs like cytarabine and gemcitabine target these polymerases to inhibit cancer cell growth (NIH: PMC2519115). Mutations in the proofreading domains of POLE and POLD1 are linked to hypermutated tumor phenotypes, which serve as important biomarkers for predicting response to immune checkpoint inhibitors (PubMed: 24022480).

Other names

Replicative DNA polymerasesFamily B DNA polymerasesDNA polymerase alpha-primase complexDNA polymerase delta complexDNA polymerase epsilon complexNuclear replicative polymerases

Inhibition of DNA synthesis through competitive binding with deoxyribonucleotide triphosphates (dNTPs), incorporation into the nascent DNA strand causing chain termination, or direct allosteric/active-site inhibition of the catalytic subunits.