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Gene Review

UL42  -  dsDNA-binding protein

Human herpesvirus 1

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Disease relevance of UL42


High impact information on UL42

  • The crystal structure of an unusual processivity factor, herpes simplex virus UL42, bound to the C terminus of its cognate polymerase [5].
  • Herpes simplex virus DNA polymerase is a heterodimer composed of a catalytic subunit, Pol, and an unusual processivity subunit, UL42, which, unlike processivity factors such as PCNA, directly binds DNA [5].
  • The crystal structure of a complex of the C-terminal 36 residues of Pol bound to residues 1-319 of UL42 reveals remarkable similarities between UL42 and PCNA despite contrasting biochemical properties and lack of sequence homology [5].
  • The details of the structure lead to a model for the mechanism of UL42, provide the basis for drug design, and allow modeling of other proteins that lack sequence homology with UL42 or PCNA [5].
  • The 36-residue peptide and a shorter peptide corresponding to the C-terminal 18 residues blocked UL42-dependent long-chain DNA synthesis at concentrations that had no effect on synthesis by the catalytic subunit alone or by calf thymus DNA polymerase delta and its processivity factor [6].

Biological context of UL42

  • Two of these genes (pol and dbp) encode well-known DNA replication proteins (the DNA polymerase and the major single-stranded DNA binding protein), and a third gene (UL42) encodes a previously identified infected-cell protein which binds tightly to double-stranded DNA [7].
  • 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 [8].
  • The mutants were not detectably affected in the ability of the polymerase to interact with its accessory protein, UL42, or to colocalize in infected cell nuclei with the major viral DNA-binding protein, ICP8, suggesting that the mutation did not exert global effects on protein folding [9].
  • Pre-steady-state and steady-state kinetics of nucleotide incorporation and excision were used to assess potential mechanisms by which the fidelity of the herpes simplex virus type 1 DNA polymerase catalytic subunit (Pol) is enhanced by its processivity factor, UL42 [10].
  • The herpes simplex virus 1 (HSV-1) UL42 protein, one of seven herpes-encoded polypeptides that are required for the replication of the HSV-1 genome, is found in a 1:1 complex with the HSV-1 DNA polymerase (Crute, J. J., and Lehman, I. R. (1989) J. Biol. Chem. 264, 19266-19270) [11].

Anatomical context of UL42

  • Using the herpes simplex virus DNA polymerase as a representative member of the alpha-polymerase family, we have recreated the association between the polymerase and its accessory protein UL42 in vitro through the translation in rabbit reticulocyte lysate of bacteriophage RNA polymerase-generated transcripts encoding the two polypeptides [12].
  • Wild-type levels of viral DNA and infectious progeny were produced in permissive V9 cells, despite the fact that V9 cells infected with Cgal delta 42 accumulated less than 1% of the UL42 RNA and protein found in Cgal+ virus-infected V9 or Vero cells [13].
  • We isolated a cell line, designated V9, stably transformed with the herpes simplex virus type 1 (HSV-1) UL42 gene, which is one of seven genes required in trans for the replication of plasmids containing an HSV origin of replication (C. A. Wu, N. J. Nelson, D. J. McGeoch, and M. D. Challberg, J. Virol. 62:435-443, 1988) [13].

Associations of UL42 with chemical compounds

  • UL42 was mixed with a maltose-binding protein-UL42 fusion protein before being added to DNA [14].
  • UL42 did not form intermolecular crosslinks upon treatment with glutaraldehyde in the presence of DNA, whereas proteins that are known to be multimers in solution were successfully crosslinked by this treatment [14].
  • The patterns of electrophoretic mobility of the resultant protein:DNA complexes were those predicted if each isoform of UL42 binds to DNA as a monomer [14].
  • Bandshift analyses revealed that the HSV pol holoenzyme-DNA complex was stably formed up to a salt concentration of 50 mM ammonium sulfate, indicating that the restricted DNA and protein interactions of both HSV pol and UL42 are responsible for the observed salt preference of the HSV pol holoenzyme under standard assay conditions in vitro [15].
  • The duplication of sequences between 94,000 np and 97,000 np results in a genome containing two copies of UL43 and one complete and one partial copy each of genes UL42 and UL44 encoding the 65 kD DNA-binding protein and glycoprotein C, respectively [16].

Physical interactions of UL42

  • 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 [8].
  • A novel functional domain of an alpha-like DNA polymerase. The binding site on the herpes simplex virus polymerase for the viral UL42 protein [12].

Other interactions of UL42

  • Taken together, the results indicate that pORF30 and pORF18 are the equine herpesvirus 1 counterparts of herpes simplex virus type 1 UL30 and UL42 and share many, but not all, of their characteristics [3].
  • Under the assay conditions employed, UL42 did not alter the rate constant for dissociation of UL9 from the DNA substrate [2].
  • 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 [2].
  • We further demonstrate that initiation of DNA synthesis can take place with a subset of these factors: Rep68 and the UL29, UL30, and UL42 gene products [17].
  • The genes UL 15 of HSV and UL 42 of VZV share the highest degree of homology within the two genomes [18].

Analytical, diagnostic and therapeutic context of UL42

  • In this report, we demonstrate that UL9 and the DNA polymerase accessory protein (UL42) can form a stable complex in vitro as determined by coimmunoprecipitation with specific antibodies to each protein and by affinity chromatography using glutathione S-transferase (GST) fusion proteins [19].
  • We used chemical crosslinking and electrophoretic mobility-shift assays to investigate whether UL42 oligomerizes upon DNA binding [14].
  • To study these interactions quantitatively, we used isothermal titration calorimetry and wild-type and mutant forms of Pol-derived peptides and UL42 [20].
  • Carboxy-terminal truncations of the UL42 protein were synthesized from restriction enzyme-digested UL42 gene templates and gene templates made by polymerase chain reaction and assayed for in vitro activity [21].
  • To measure the contribution of the C terminus of POL to UL42 binding we developed a competition ELISA using POL, a truncated polymerase lacking the carboxyl-terminal 27 amino acids (POLd1) and UL42 [22].


  1. Effects of substitutions of arginine residues on the basic surface of herpes simplex virus UL42 support a role for DNA binding in processive DNA synthesis. Randell, J.C., Komazin, G., Jiang, C., Hwang, C.B., Coen, D.M. J. Virol. (2005) [Pubmed]
  2. 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]
  3. Cloning, expression, and functional characterization of the equine herpesvirus 1 DNA polymerase and its accessory subunit. Loregian, A., Case, A., Cancellotti, E., Valente, C., Marsden, H.S., Palù, G. J. Virol. (2006) [Pubmed]
  4. The UL8 subunit of the herpes simplex virus helicase-primase complex is required for efficient primer utilization. Sherman, G., Gottlieb, J., Challberg, M.D. J. Virol. (1992) [Pubmed]
  5. The crystal structure of an unusual processivity factor, herpes simplex virus UL42, bound to the C terminus of its cognate polymerase. Zuccola, H.J., Filman, D.J., Coen, D.M., Hogle, J.M. Mol. Cell (2000) [Pubmed]
  6. Specific inhibition of herpes simplex virus DNA polymerase by helical peptides corresponding to the subunit interface. Digard, P., Williams, K.P., Hensley, P., Brooks, I.S., Dahl, C.E., Coen, D.M. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  7. Herpes simplex virus type 1 gene products required for DNA replication: identification and overexpression. Olivo, P.D., Nelson, N.J., Challberg, M.D. J. Virol. (1989) [Pubmed]
  8. 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]
  9. Polymerization activity of an alpha-like DNA polymerase requires a conserved 3'-5' exonuclease active site. Gibbs, J.S., Weisshart, K., Digard, P., deBruynKops, A., Knipe, D.M., Coen, D.M. Mol. Cell. Biol. (1991) [Pubmed]
  10. The herpes simplex virus type 1 DNA polymerase processivity factor increases fidelity without altering pre-steady-state rate constants for polymerization or excision. Chaudhuri, M., Song, L., Parris, D.S. J. Biol. Chem. (2003) [Pubmed]
  11. Functional interaction between the herpes simplex-1 DNA polymerase and UL42 protein. Hernandez, T.R., Lehman, I.R. J. Biol. Chem. (1990) [Pubmed]
  12. A novel functional domain of an alpha-like DNA polymerase. The binding site on the herpes simplex virus polymerase for the viral UL42 protein. Digard, P., Coen, D.M. J. Biol. Chem. (1990) [Pubmed]
  13. Isolation of a herpes simplex virus type 1 mutant deleted for the essential UL42 gene and characterization of its null phenotype. Johnson, P.A., Best, M.G., Friedmann, T., Parris, D.S. J. Virol. (1991) [Pubmed]
  14. The herpes simplex virus processivity factor, UL42, binds DNA as a monomer. Randell, J.C., Coen, D.M. J. Mol. Biol. (2004) [Pubmed]
  15. DNA and protein interactions of the small subunit of herpes simplex virus type 1 DNA polymerase. Franz, C., Kühn, F.J., Knopf, C.W. Virology (1999) [Pubmed]
  16. A HSV-1 variant (1720) generates four equimolar isomers despite a 9200-bp deletion from TRL and sequences between 9200 np and 97,000 np in inverted orientation being covalently bound to sequences 94,000-126,372 np. Harland, J., Brown, S.M. Virus Genes (1992) [Pubmed]
  17. Rep-dependent initiation of adeno-associated virus type 2 DNA replication by a herpes simplex virus type 1 replication complex in a reconstituted system. Ward, P., Falkenberg, M., Elias, P., Weitzman, M., Linden, R.M. J. Virol. (2001) [Pubmed]
  18. Evaluation of a new general primer pair for rapid detection and differentiation of HSV-1, HSV-2, and VZV by polymerase chain reaction. Baron, J.M., Rübben, A., Grussendorf-Conen, E.I. J. Med. Virol. (1996) [Pubmed]
  19. 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]
  20. Identification of crucial hydrogen-bonding residues for the interaction of herpes simplex virus DNA polymerase subunits via peptide display, mutational, and calorimetric approaches. Bridges, K.G., Chow, C.S., Coen, D.M. J. Virol. (2001) [Pubmed]
  21. Deletions of the carboxy terminus of herpes simplex virus type 1 UL42 define a conserved amino-terminal functional domain. Tenney, D.J., Hurlburt, W.W., Bifano, M., Stevens, J.T., Micheletti, P.A., Hamatake, R.K., Cordingley, M.G. J. Virol. (1993) [Pubmed]
  22. Role of the carboxy terminus of herpes simplex virus type 1 DNA polymerase in its interaction with UL42. Marsden, H.S., Murphy, M., McVey, G.L., MacEachran, K.A., Owsianka, A.M., Stow, N.D. J. Gen. Virol. (1994) [Pubmed]
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