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Gene Review

UL9  -  DNA replication origin-binding helicase

Human herpesvirus 1

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Disease relevance of UL9

  • Functional analyses of UL9 and the helicase-primase complex will be discussed with attention to the roles these proteins play during HSV-1 replication [1].
  • The herpes simplex virus type 1 UL42 DNA polymerase processivity factor interacts physically with UL9 and enhances its ability to unwind short, partially duplex DNA [2].
  • We have expressed the product of one of these genes, UL9, in insect cells by using a baculovirus expression vector [3].
  • Herpes simplex virus DNA replication: the UL9 gene encodes an origin-binding protein [3].
  • The C-terminal 317 amino acids of the UL9 gene expressed as a fusion protein in Escherichia coli also bound to the origin [4].

High impact information on UL9

  • The neural F-box protein NFB42 mediates the nuclear export of the herpes simplex virus type 1 replication initiator protein (UL9 protein) after viral infection [5].
  • Because the intranuclear localization of the UL9 protein, along with other viral and cellular factors, is an essential step in viral DNA replication, degradation of the UL9 protein in neurons by means of nuclear export through its specific interaction with NFB42 may prevent active replication and promote neuronal latency of HSV-1 [5].
  • This interaction mediates the export of the UL9 protein from the nucleus to the cytosol, leading to its ubiquitination and degradation via the 26S proteasome [5].
  • These include the viral origin-binding protein, UL9, and single-strand binding protein ICP8, host cell topoisomerase I, and superhelicity of the DNA template [6].
  • We have identified cellular proteins that interact with the herpes simplex virus type 1 (HSV-1) origin-binding protein (UL9 protein) by screening a HeLa cell complementary DNA library by using the yeast two-hybrid system [7].

Chemical compound and disease context of UL9

  • To determine the effect of the major DNA adduct, the intrastrand d(GpG) cross-link, produced by the antitumor drug cis-diamminedichloroplatinum(II) on the activity of a helicase known to be essential for DNA replication, we have examined its interaction with the origin-binding protein (UL9 protein) of herpes simplex virus type-1 [8].
  • By using a tetracycline repressor (tetR)-mediated HSV-1 viral replication switch [Yao and Eriksson (1999). Hum. Gene Ther. 10, 419-427], we have generated a novel anti-HSV-1-specific HSV-1 recombinant (CJ83193) that expresses a trans-dominant negative HSV-1 UL9 origin-binding protein, UL9-C535C [9].
  • A double-stranded oligonucleotide was designed with a target site for the binding of a pyrimidine oligonucleotide located immediately adjacent to the recognition sequence for the herpes simplex virus type 1 (HSV-1) origin of replication binding protein, which is encoded by the UL9 gene of HSV-1 [10].
  • Transient expression analyses show that dibutyryl cyclic AMP, known to elevate intracellular cAMP level, can induce the UL9 promoter in a rat pheochromocytoma cell line (PC12) but not in a non-neuronal human cell line (HeLa) [11].
  • A live attenuated HSV-1 (deleted in the gE gene), and a HSV-1 (strain HSZP)-infected cell extract served as positive controls, and three non-structural recombinant HSV-1 fusion proteins (ICP27, UL9/OBP and thymidine kinase--TK) were used as presumed non-protective (negative) controls [12].

Biological context of UL9

  • UL9 binds specifically to the origins of replication and is believed to initiate DNA replication at one of three origins of replication located in the HSV-1 genome [1].
  • Our studies reveal that a homodimer of UL9 is sufficient for DNA translocation coupled to ATP hydrolysis, and the steady-state ATPase catalytic rate was greater on partially duplex DNA than on ss DNA in the presence or absence of UL42 [2].
  • However, an additional gene coding for an HSV origin-binding protein (UL9) was required for origin-dependent HSV DNA replication but was dispensible for SV40 DNA amplification [13].
  • Examination of the nucleotide sequence of the UL8.5 transcript revealed a potential open reading frame that overlaps and is in frame with the C-terminal half of the open reading frame encoding the origin-binding protein (OBP), the product of the UL9 gene [14].
  • These include a heterodimeric DNA polymerase, a single-strand-DNA-binding protein, a heterotrimeric helicase/primase, and a protein (UL9 protein) that binds specifically to an HSV-1 origin of replication (oris) [15].

Anatomical context of UL9

  • The UL9 protein (origin-binding protein) efficiently entered the cell nucleus when expressed alone [16].
  • Affinity beads charged with increasing concentrations of GST-42 fusion protein up to 5 microM bound increasing amounts of UL9 expressed by in vitro transcription/translation in rabbit reticulocyte lysates [17].
  • The apparent size of the UL9 protein, both in insect cells and in herpes simplex virus-infected Vero cells, is 82,000 Da [3].
  • These defects are complemented efficiently by growth in the permissive cell line, S22, which contains the wild type version of several HSV genes including UL9 [18].
  • Genetic analysis of the herpes simplex virus type 1 UL9 gene: isolation of a LacZ insertion mutant and expression in eukaryotic cells [18].

Associations of UL9 with chemical compounds

  • Accordingly, sensitivity of UL9 protein to N-ethylmaleimide is due to at least two cysteines [19].
  • KMnO4 and dimethyl sulfate footprinting further show that UL9 alters the DNA helix in the AT region [20].
  • Since the optimal conditions for the binding of the UL9 protein and the pyrimidine oligonucleotide to the duplex DNA are markedly different, a pyrimidine oligonucleotide was designed to optimize binding affinity and specificity for the target duplex oligonucleotide [10].
  • Various regions of UL9 were tested in fusion constructs for their ability to direct the normally cytoplasmic chicken pyruvate kinase protein to the nucleus [21].
  • Moreover, alteration of a lysine residue 18 amino acids from the recognized peptide prevented the interaction of MAb 13924 with the UL9 C-terminal DNA-binding domain [22].

Physical interactions of UL9


Regulatory relationships of UL9

  • The different means by which ICP8 and UL42 enhance the ability of UL9 to unwind DNA suggest that these two members of the presumed functional replisome may act synergistically on UL9 to effect initiation of HSV-1 DNA replication in vivo [23].
  • 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 [24].

Other interactions of UL9

  • These data support a model whereby UL42 increases the ability of UL9 to load onto DNA, thus increasing its ability to assemble into a functional complex capable of unwinding duplex DNA [2].
  • In contrast, UL52 protein was transported to the nucleus in BHK cells infected with wild-type HSV-1 or with 2-2, a mutant lacking a functional UL9 protein [25].
  • The 3' ends of the UL8, UL8.5, UL9, and UL9.5 transcripts are coterminal at nucleotide 18,197 [14].
  • From the analysis of mutants lacking both UL5 and UL9, we conclude that neither viral helicase is required for the prereplicative site pattern to form as long as a polymerase inhibitor is present [26].
  • However, to date, no interaction between UL9 and a component of the DNA polymerase holoenzyme has been demonstrated [17].

Analytical, diagnostic and therapeutic context of UL9


  1. The two helicases of herpes simplex virus type 1 (HSV-1). Chattopadhyay, S., Chen, Y., Weller, S.K. Front. Biosci. (2006) [Pubmed]
  2. The herpes simplex virus type 1 DNA polymerase processivity factor, UL42, does not alter the catalytic activity of the UL9 origin-binding protein but facilitates its loading onto DNA. Trego, K.S., Zhu, Y., Parris, D.S. Nucleic Acids Res. (2005) [Pubmed]
  3. Herpes simplex virus DNA replication: the UL9 gene encodes an origin-binding protein. Olivo, P.D., Nelson, N.J., Challberg, M.D. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  4. Binding of the herpes simplex virus type 1 UL9 gene product to an origin of viral DNA replication. Weir, H.M., Calder, J.M., Stow, N.D. Nucleic Acids Res. (1989) [Pubmed]
  5. The neural F-box protein NFB42 mediates the nuclear export of the herpes simplex virus type 1 replication initiator protein (UL9 protein) after viral infection. Eom, C.Y., Heo, W.D., Craske, M.L., Meyer, T., Lehman, I.R. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  6. Origin-specific unwinding of herpes simplex virus 1 DNA by the viral UL9 and ICP8 proteins: visualization of a specific preunwinding complex. Makhov, A.M., Lee, S.S., Lehman, I.R., Griffith, J.D. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  7. The human DnaJ protein, hTid-1, enhances binding of a multimer of the herpes simplex virus type 1 UL9 protein to oris, an origin of viral DNA replication. Eom, C.Y., Lehman, I.R. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  8. Effect of the major DNA adduct of the antitumor drug cis-diamminedichloroplatinum (II) on the activity of a helicase essential for DNA replication, the herpes simplex virus type-1 origin-binding protein. Villani, G., Pillaire, M.J., Boehmer, P.E. J. Biol. Chem. (1994) [Pubmed]
  9. A novel anti-herpes simplex virus type 1-specific herpes simplex virus type 1 recombinant. Yao, F., Eriksson, E. Hum. Gene Ther. (1999) [Pubmed]
  10. Triple-helix formation is compatible with an adjacent DNA-protein complex. Huang, C.C., Nguyen, D., Martinez, R., Edwards, C.A. Biochemistry (1992) [Pubmed]
  11. Cell-type-specific induction of the UL9 gene of HSV-1 by cell signaling pathway. Deb, S.P., Deb, S., Brown, D.R. Biochem. Biophys. Res. Commun. (1994) [Pubmed]
  12. Efficacy of recombinant herpes simplex virus 1 glycoprotein D candidate vaccines in mice. Durmanová, V., Mosko, T., Sapák, M., Kosovský, J., Rezuchová, I., Buc, M., Rajcáni, J. Acta microbiologica et immunologica Hungarica (2006) [Pubmed]
  13. A subset of herpes simplex virus replication genes induces DNA amplification within the host cell genome. Heilbronn, R., zur Hausen, H. J. Virol. (1989) [Pubmed]
  14. 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]
  15. Interaction of herpes simplex virus 1 origin-binding protein with DNA polymerase alpha. Lee, S.S., Dong, Q., Wang, T.S., Lehman, I.R. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  16. On the cellular localization of the components of the herpes simplex virus type 1 helicase-primase complex and the viral origin-binding protein. Calder, J.M., Stow, E.C., Stow, N.D. J. Gen. Virol. (1992) [Pubmed]
  17. Interaction between the herpes simplex virus type 1 origin-binding and DNA polymerase accessory proteins. Monahan, S.J., Grinstead, L.A., Olivieri, W., Parris, D.S. Virology (1998) [Pubmed]
  18. Genetic analysis of the herpes simplex virus type 1 UL9 gene: isolation of a LacZ insertion mutant and expression in eukaryotic cells. Malik, A.K., Martinez, R., Muncy, L., Carmichael, E.P., Weller, S.K. Virology (1992) [Pubmed]
  19. Cysteine 111 affects coupling of single-stranded DNA binding to ATP hydrolysis in the herpes simplex virus type-1 origin-binding protein. Sampson, D.A., Arana, M.E., Boehmer, P.E. J. Biol. Chem. (2000) [Pubmed]
  20. Herpes simplex virus origin-binding protein (UL9) loops and distorts the viral replication origin. Koff, A., Schwedes, J.F., Tegtmeyer, P. J. Virol. (1991) [Pubmed]
  21. Intracellular localization of the herpes simplex virus type-1 origin binding protein, UL9. Malik, A.K., Shao, L., Shanley, J.D., Weller, S.K. Virology (1996) [Pubmed]
  22. Identification of residues within the herpes simplex virus type 1 origin-binding protein that contribute to sequence-specific DNA binding. Stow, N.D., Brown, G., Cross, A.M., Abbotts, A.P. Virology (1998) [Pubmed]
  23. 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]
  24. 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]
  25. 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]
  26. Herpes simplex virus type 1 prereplicative sites are a heterogeneous population: only a subset are likely to be precursors to replication compartments. Lukonis, C.J., Burkham, J., Weller, S.K. J. Virol. (1997) [Pubmed]
  27. The herpes simplex virus type 1 origin-binding protein carries out origin specific DNA unwinding and forms stem-loop structures. Makhov, A.M., Boehmer, P.E., Lehman, I.R., Griffith, J.D. EMBO J. (1996) [Pubmed]
  28. Visualization of the unwinding of long DNA chains by the herpes simplex virus type 1 UL9 protein and ICP8. Makhov, A.M., Boehmer, P.E., Lehman, I.R., Griffith, J.D. J. Mol. Biol. (1996) [Pubmed]
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