DNA-directed DNA polymerase alpha, delta, and epsilon (Pol α, Pol δ, Pol ε) (Pol α, Pol δ, Pol ε)

DNA-directed DNA polymerases alpha, delta, and epsilon are the primary enzymes responsible for the high-fidelity replication of the eukaryotic nuclear genome [1]. DNA polymerase alpha (Pol α) initiates the process by synthesizing short RNA-DNA primers, which are subsequently elongated by DNA polymerase delta (Pol δ) on the lagging strand and DNA polymerase epsilon (Pol ε) on the leading strand [2][3]. These enzymes are essential for maintaining genomic integrity, with Pol δ and Pol ε possessing intrinsic 3' to 5' exonuclease activity for proofreading mismatched bases [4]. In oncology, these polymerases are the principal targets of nucleoside analog chemotherapies, which disrupt DNA synthesis in rapidly dividing cells to trigger programmed cell death [5]. Furthermore, mutations in the proofreading domains of the POLE and POLD1 genes are associated with hypermutated phenotypes in various cancers, serving as critical biomarkers for identifying patients likely to respond to immune checkpoint inhibitors [6].

Other names

DNA polymerase alpha and other replicative DNA polymerasesReplicative DNA polymerasesDNA polymerase complexPOLA1POLD1POLEEukaryotic replicative polymerases

Nucleoside analogs act as antimetabolites that are phosphorylated into active triphosphate forms; these compete with natural deoxynucleotide triphosphates (dNTPs) for incorporation into the nascent DNA strand by replicative polymerases, leading to DNA chain termination, replication fork stalling, and the induction of apoptosis.