DNA polymerase alpha (POLA) (POLA)

DNA polymerase alpha (POLA) is a critical enzyme complex in eukaryotic cells responsible for initiating DNA replication by synthesizing RNA-DNA primers. It plays a fundamental role in the S phase of the cell cycle, ensuring the accurate duplication of the host genome. In clinical pharmacology, host DNA polymerases are significant off-targets for nucleoside analog antivirals like ganciclovir. Ganciclovir is converted by viral and host kinases into ganciclovir triphosphate (GCV-TP), which structurally resembles deoxyguanosine triphosphate (dGTP). GCV-TP competitively inhibits the incorporation of dGTP into the growing DNA strand by host DNA polymerase alpha, albeit with lower affinity than for viral polymerases (PubChem CID 3454). This inhibition leads to the slowing or termination of DNA chain elongation, which can halt cell division in rapidly proliferating host tissues. The primary clinical consequence of this interaction is myelosuppression, manifesting as severe neutropenia, anemia, and thrombocytopenia (StatPearls NBK554403). Because of this off-target effect, ganciclovir has a narrow therapeutic index and requires close monitoring of hematologic parameters (DrugBank DB00449).

Other names

DNA-directed DNA polymerase alphaHost cellular DNA polymerasePOLA1DNA polymerase alpha catalytic subunitDNA polymerase alpha complex

Competitive inhibition of deoxyguanosine triphosphate (dGTP) incorporation into DNA, leading to DNA chain termination or slowing of elongation.