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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
Gene Review

UL8  -  helicase-primase subunit

Human herpesvirus 1

 
 
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Disease relevance of UL8

  • The UL8 subunit of the herpes simplex virus type-1 DNA helicase-primase optimizes utilization of DNA templates covered by the homologous single-strand DNA-binding protein ICP8 [1].
  • Similar experiments using a recombinant virus that expressed the HSV-1 origin-binding protein (OBP), UL9, demonstrated a direct physical interaction between the helicase-primase complex and OBP which involved the UL8 subunit [2].
  • UL8 protein was purified from insect cells infected with a recombinant baculovirus and used to generate monoclonal antibodies (MAbs) [2].
  • To further our understanding of UL8, we have constructed plasmids expressing mutant proteins, truncated at their N- or C-termini or lacking amino acids internally, under the control of the human cytomegalovirus major immediate-early promoter [3].
 

High impact information on UL8

  • The purified UL8 gene product, although required for viral DNA replication, neither exhibits these enzymatic activities nor stably associates with either the UL5 or the UL52 gene product [4].
  • Herpes simplex virus type 1 encodes a heterotrimeric helicase-primase complex composed of the products of the UL5, UL52, and UL8 genes [5].
  • The UL8 subunit of the heterotrimeric herpes simplex virus type 1 helicase-primase is required for the unwinding of single strand DNA-binding protein (ICP8)-coated DNA substrates [6].
  • These data suggest that UL8 protein mediates an interaction between the UL5/52 core enzyme and ICP8 that optimizes the utilization of ICP8-covered DNA templates during DNA replication [1].
  • UL8 did not affect the amount or size of primers annealed to template, their utilization by DNA polymerase, or the use of specific initiation sites within the template [7].
 

Biological context of UL8

  • We have mapped and characterized the overlapping transcripts in this region and have found that, in addition to the low-abundance UL8 and UL9 transcripts and the abundant UL10 transcript, at least two additional transcription units, designated UL8.5 and UL9.5, are specified by this region of the genome [8].
  • None of the UL8 mutants tested exhibited a strong dominant negative phenotype in the presence of the wild-type product, although some inhibition of replication was observed with mutants lacking 165 N-terminal or 497 C-terminal amino acids [3].
  • Deletion of 23 amino acids from the N-terminus or 33 from the C-terminus abolished the ability of UL8 to support DNA replication in transient transfection assays [3].
 

Physical interactions of UL8

  • Deletion analysis showed that a 548 amino acid fragment of UL52 (amino acids 366-914) retains the ability to interact with UL8 and that the N-terminal 349 amino acids are dispensable for the interaction [9].
 

Regulatory relationships of UL8

  • The herpes simplex virus type 1 UL8 protein influences the intracellular localization of the UL52 but not the ICP8 or POL replication proteins in virus-infected cells [10].
  • By the use of HSV mutants for the UL9 gene we show here that HSV can induce DNA amplification in the absence of lytic viral growth in contrast to replication-negative mutants for either the UL8 or UL52 gene used as control [11].
 

Other interactions of UL8

  • The heterotrimeric helicase-primase complex, encoded by the UL5, UL8 and UL52 genes, is believed to unwind duplex viral DNA at replication forks and to prime lagging strand synthesis [12].
  • The origin (ori)-binding protein of herpes simplex virus type 1 (HSV-1), encoded by the UL9 open reading frame, has been shown to physically interact with a number of cellular and viral proteins, including three HSV-1 proteins (ICP8, UL42, and UL8) essential for ori-dependent DNA replication [13].
  • The 3' ends of the UL8, UL8.5, UL9, and UL9.5 transcripts are coterminal at nucleotide 18,197 [8].
  • Transcriptional analysis of the region of the herpes simplex virus type 1 genome containing the UL8, UL9, and UL10 genes and identification of a novel delayed-early gene product, OBPC [8].
 

Analytical, diagnostic and therapeutic context of UL8

  • On the other hand, the mutant protein retains its ability to interact with UL5 as indicated by copurification and with UL8 as indicated by a supershifted band in the gel mobility shift assay [14].
  • Surface plasmon resonance measurements demonstrated an interaction between ICP8 and the UL5/52/8 heterotrimer but not with the UL5/52 subassembly or the UL8 protein alone [6].
  • The ability of the UL8 mutants to facilitate efficient nuclear localization of UL52 in the presence of coexpressed UL5 was examined by immunofluorescence [3].

References

  1. The UL8 subunit of the herpes simplex virus type-1 DNA helicase-primase optimizes utilization of DNA templates covered by the homologous single-strand DNA-binding protein ICP8. Tanguy Le Gac, N., Villani, G., Hoffmann, J.S., Boehmer, P.E. J. Biol. Chem. (1996) [Pubmed]
  2. The herpes simplex virus type 1 origin-binding protein interacts specifically with the viral UL8 protein. McLean, G.W., Abbotts, A.P., Parry, M.E., Marsden, H.S., Stow, N.D. J. Gen. Virol. (1994) [Pubmed]
  3. Deletion mutants of the herpes simplex virus type 1 UL8 protein: effect on DNA synthesis and ability to interact with and influence the intracellular localization of the UL5 and UL52 proteins. Barnard, E.C., Brown, G., Stow, N.D. Virology (1997) [Pubmed]
  4. Association of DNA helicase and primase activities with a subassembly of the herpes simplex virus 1 helicase-primase composed of the UL5 and UL52 gene products. Dodson, M.S., Lehman, I.R. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  5. The UL5 and UL52 subunits of the herpes simplex virus type 1 helicase-primase subcomplex exhibit a complex interdependence for DNA binding. Biswas, N., Weller, S.K. J. Biol. Chem. (2001) [Pubmed]
  6. The UL8 subunit of the heterotrimeric herpes simplex virus type 1 helicase-primase is required for the unwinding of single strand DNA-binding protein (ICP8)-coated DNA substrates. Falkenberg, M., Bushnell, D.A., Elias, P., Lehman, I.R. J. Biol. Chem. (1997) [Pubmed]
  7. The UL8 component of the herpes simplex virus helicase-primase complex stimulates primer synthesis by a subassembly of the UL5 and UL52 components. Tenney, D.J., Hurlburt, W.W., Micheletti, P.A., Bifano, M., Hamatake, R.K. J. Biol. Chem. (1994) [Pubmed]
  8. Transcriptional analysis of the region of the herpes simplex virus type 1 genome containing the UL8, UL9, and UL10 genes and identification of a novel delayed-early gene product, OBPC. Baradaran, K., Dabrowski, C.E., Schaffer, P.A. J. Virol. (1994) [Pubmed]
  9. Two-hybrid analysis of the interaction between the UL52 and UL8 subunits of the herpes simplex virus type 1 helicase-primase. Constantin, N., Dodson, M.S. J. Gen. Virol. (1999) [Pubmed]
  10. The herpes simplex virus type 1 UL8 protein influences the intracellular localization of the UL52 but not the ICP8 or POL replication proteins in virus-infected cells. Marsden, H.S., Cross, A.M., Francis, G.J., Patel, A.H., MacEachran, K., Murphy, M., McVey, G., Haydon, D., Abbotts, A., Stow, N.D. J. Gen. Virol. (1996) [Pubmed]
  11. Herpes simplex virus type 1 mutants for the origin-binding protein induce DNA amplification in the absence of viral replication. Heilbronn, R., Weller, S.K., zur Hausen, H. Virology (1990) [Pubmed]
  12. The two helicases of herpes simplex virus type 1 (HSV-1). Chattopadhyay, S., Chen, Y., Weller, S.K. Front. Biosci. (2006) [Pubmed]
  13. Functional interaction between the herpes simplex virus type 1 polymerase processivity factor and origin-binding proteins: enhancement of UL9 helicase activity. Trego, K.S., Parris, D.S. J. Virol. (2003) [Pubmed]
  14. A mutation in the C-terminal putative Zn2+ finger motif of UL52 severely affects the biochemical activities of the HSV-1 helicase-primase subcomplex. Biswas, N., Weller, S.K. J. Biol. Chem. (1999) [Pubmed]
 
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