Herpes simplex virus 1 DNA polymerase (HSV-1 Pol (UL30))

The **Herpes simplex virus 1 DNA polymerase** (HSV-1 Pol, encoded by UL30) is a family B replicative enzyme essential for viral genome duplication during lytic infection of its 152 kb double-stranded DNA genome. It forms a heterodimeric holoenzyme with the UL42 processivity factor, enabling processive leading and lagging strand synthesis in coordination with the helicase-primase complex (UL5-UL8-UL52) and single-stranded DNA-binding protein (UL29/ICP8). Beyond polymerization, it possesses 3'-5' exonuclease proofreading, intrinsic RNase H activity for RNA-DNA hybrid cleavage, and apurinic/apyrimidinic (AP) endonuclease plus 5'-deoxyribose phosphate (dRP) lyase activities supporting viral base excision repair. In HSV-1 infection, particularly herpes labialis, keratitis, and encephalitis, this polymerase drives pathogenesis by amplifying viral DNA in epithelial and neuronal cells. It is a validated antiviral target, inhibited by nucleoside analogs like acyclovir (chain terminator after phosphorylation by viral thymidine kinase) and pyrophosphate mimics like foscarnet, though resistance arises via mutations altering conformational dynamics or drug binding. Inhibition can trigger host S-phase DNA damage responses, including replication protein A hyperphosphorylation at stalled forks, highlighting therapeutic challenges. Crystal and cryo-EM structures reveal its thumb, fingers, palm domains gripping DNA, with drugs exploiting closed conformations for selectivity.

Other names

UL30HSV-1 polymerasePol

Nucleoside analog chain termination, Non-nucleoside inhibition at polymerase active site, Pyrophosphate analog inhibition of polymerization