Host DNA polymerases (DNA polymerase alpha, delta, and epsilon) (Pol α, Pol δ, Pol ε)

Host DNA polymerases, specifically the alpha (Pol α), delta (Pol δ), and epsilon (Pol ε) isoforms, are the fundamental enzymes responsible for replicating the eukaryotic genome during the S-phase of the cell cycle. Polyomaviruses, such as the BK virus and JC virus, possess small double-stranded DNA genomes that do not encode a viral DNA polymerase, making them entirely dependent on the host's replication machinery for viral progeny production (PubMed: 25135935). The viral Large T-antigen facilitates this hijacking by acting as a helicase and recruiting the host Pol α-primase complex to the viral origin of replication to initiate synthesis (UniProt: P03070). Subsequently, Pol δ and Pol ε are utilized for processive leading and lagging strand synthesis of the viral DNA. Because these enzymes are essential for host cell survival, they are difficult to target selectively; however, nucleotide analogs like cidofovir are used clinically to inhibit viral replication by interfering with the synthesis process (StatPearls: NBK545234). The primary therapeutic challenge lies in the fact that inhibiting these polymerases often results in significant systemic toxicity, such as nephrotoxicity and bone marrow suppression, due to the simultaneous inhibition of normal host DNA synthesis.

Other names

Eukaryotic replicative DNA polymerasesDNA-directed DNA polymerase complexReplicative DNA polymerase alphaReplicative DNA polymerase deltaReplicative DNA polymerase epsilon

Inhibition of DNA chain elongation through competitive inhibition with natural deoxynucleotide triphosphates (dNTPs) or via DNA chain termination upon incorporation into the nascent DNA strand.