Herpesviral helicase-primase subunit UL8 is inactivated B-family polymerase

Bioinformatics. 2014 Aug 1;30(15):2093-7. doi: 10.1093/bioinformatics/btu204. Epub 2014 Apr 18.


Motivation: Herpesviruses are large DNA viruses causing a variety of diseases in humans and animals. To develop effective treatment, it is important to understand the mechanisms of their replication. One of the components of the herpesviral DNA replication system is a helicase-primase complex, consisting of UL5 (helicase), UL52 (primase) and UL8. UL8 is an essential herpesviral protein involved in multiple protein-protein interactions. Intriguingly, so far no UL8 homologs outside of herpesviruses could be identified. Moreover, nothing is known about its structure or domain organization.

Results: Here, combining sensitive homology detection methods and homology modeling, we found that the UL8 protein family is related to B-family polymerases. In the course of evolution, UL8 has lost the active site and has undergone a reduction of DNA-binding motifs. The loss of active site residues explains the failure to detect any catalytic activity of UL8. A structural model of human herpes virus 1 UL8 constructed as part of the study is consistent with the mutation data targeting its interaction with primase UL52. It also provides a platform for studying multiple interactions that UL8 is involved in. The two other components of helicase-primase complex show evolutionary links with a newly characterized human primase that also has DNA polymerase activity (PrimPol) and the Pif1 helicase, respectively. The role of these enzymes in recovering stalled replication forks suggests mechanistic and functional similarities with herpesviral proteins.

Contact: venclovas@ibt.lt

Supplementary information: Supplementary data are available at Bioinformatics online.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Binding Sites
  • Computational Biology
  • Conserved Sequence
  • DNA Helicases / chemistry*
  • DNA Helicases / metabolism*
  • DNA Primase / chemistry*
  • DNA Primase / metabolism*
  • DNA Replication
  • DNA-Directed DNA Polymerase / chemistry
  • DNA-Directed DNA Polymerase / metabolism*
  • Enzyme Activation
  • Evolution, Molecular
  • Herpesvirus 1, Human / enzymology*
  • Herpesvirus 1, Human / physiology
  • Humans
  • Models, Molecular
  • Multifunctional Enzymes / chemistry
  • Multifunctional Enzymes / metabolism
  • Viral Proteins / chemistry*
  • Viral Proteins / metabolism*
  • Virus Replication


  • Multifunctional Enzymes
  • Viral Proteins
  • DNA Primase
  • PrimPol protein, human
  • DNA-Directed DNA Polymerase
  • helicase-primase, Human herpesvirus 1
  • DNA Helicases
  • PIF1 protein, human