Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1997 Mar;71(3):2031–2040. doi: 10.1128/jvi.71.3.2031-2040.1997

Repression of host RNA polymerase II transcription by herpes simplex virus type 1.

C A Spencer 1, M E Dahmus 1, S A Rice 1
PMCID: PMC191289  PMID: 9032335

Abstract

Lytic infection of mammalian cells with herpes simplex virus type 1 (HSV-1) results in rapid repression of host gene expression and selective activation of the viral genome. This transformation in gene expression is thought to involve repression of host transcription and diversion of the host RNA polymerase (RNAP II) transcription machinery to the viral genome. However, the extent of virus-induced host transcription repression and the mechanisms responsible for these major shifts in transcription specificities have not been examined. To determine how HSV-1 accomplishes repression of host RNAP II transcription, we assayed transcription patterns on several cellular genes in cells infected with mutant and wild-type HSV-1. Our results suggest that HSV-1 represses RNAP II transcription on most cellular genes. However, each cellular gene we examined responds differently to the transcription repressive effects of virus infection, both quantitatively and with respect to the involvement of viral gene products. Virus-induced shutoff of host RNAP II transcription requires expression of multiple immediate-early genes. In contrast, expression of delayed-early and late genes and viral DNA replication appear to contribute little to repression of host cell RNAP II transcription. Modification of RNAP II to the intermediately phosphorylated (II(I)) form appears unlinked to virus-induced repression of host cell transcription. However, full repression of host transcription is correlated with depletion of the hyperphosphorylated (IIO) form of RNAP II.

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arcari P., Martinelli R., Salvatore F. The complete sequence of a full length cDNA for human liver glyceraldehyde-3-phosphate dehydrogenase: evidence for multiple mRNA species. Nucleic Acids Res. 1984 Dec 11;12(23):9179–9189. doi: 10.1093/nar/12.23.9179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bartholomew B., Dahmus M. E., Meares C. F. RNA contacts subunits IIo and IIc in HeLa RNA polymerase II transcription complexes. J Biol Chem. 1986 Oct 25;261(30):14226–14231. [PubMed] [Google Scholar]
  3. Bentley D. L., Brown W. L., Groudine M. Accurate, TATA box-dependent polymerase III transcription from promoters of the c-myc gene in injected Xenopus oocytes. Genes Dev. 1989 Aug;3(8):1179–1189. doi: 10.1101/gad.3.8.1179. [DOI] [PubMed] [Google Scholar]
  4. Bentley D. L., Groudine M. A block to elongation is largely responsible for decreased transcription of c-myc in differentiated HL60 cells. Nature. 1986 Jun 12;321(6071):702–706. doi: 10.1038/321702a0. [DOI] [PubMed] [Google Scholar]
  5. Cadena D. L., Dahmus M. E. Messenger RNA synthesis in mammalian cells is catalyzed by the phosphorylated form of RNA polymerase II. J Biol Chem. 1987 Sep 15;262(26):12468–12474. [PubMed] [Google Scholar]
  6. Carrozza M. J., DeLuca N. A. Interaction of the viral activator protein ICP4 with TFIID through TAF250. Mol Cell Biol. 1996 Jun;16(6):3085–3093. doi: 10.1128/mcb.16.6.3085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chung J., Sussman D. J., Zeller R., Leder P. The c-myc gene encodes superimposed RNA polymerase II and III promoters. Cell. 1987 Dec 24;51(6):1001–1008. doi: 10.1016/0092-8674(87)90586-1. [DOI] [PubMed] [Google Scholar]
  8. Cook W. J., Coen D. M. Temporal regulation of herpes simplex virus type 1 UL24 mRNA expression via differential polyadenylation. Virology. 1996 Apr 1;218(1):204–213. doi: 10.1006/viro.1996.0180. [DOI] [PubMed] [Google Scholar]
  9. Corden J. L. RNA polymerase II transcription cycles. Curr Opin Genet Dev. 1993 Apr;3(2):213–218. doi: 10.1016/0959-437x(93)90025-k. [DOI] [PubMed] [Google Scholar]
  10. Dahmus M. E. Reversible phosphorylation of the C-terminal domain of RNA polymerase II. J Biol Chem. 1996 Aug 9;271(32):19009–19012. doi: 10.1074/jbc.271.32.19009. [DOI] [PubMed] [Google Scholar]
  11. Dahmus M. E. The role of multisite phosphorylation in the regulation of RNA polymerase II activity. Prog Nucleic Acid Res Mol Biol. 1994;48:143–179. doi: 10.1016/s0079-6603(08)60855-7. [DOI] [PubMed] [Google Scholar]
  12. DeLuca N. A., Schaffer P. A. Activation of immediate-early, early, and late promoters by temperature-sensitive and wild-type forms of herpes simplex virus type 1 protein ICP4. Mol Cell Biol. 1985 Aug;5(8):1997–2008. doi: 10.1128/mcb.5.8.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Erba H. P., Eddy R., Shows T., Kedes L., Gunning P. Structure, chromosome location, and expression of the human gamma-actin gene: differential evolution, location, and expression of the cytoskeletal beta- and gamma-actin genes. Mol Cell Biol. 1988 Apr;8(4):1775–1789. doi: 10.1128/mcb.8.4.1775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Godowski P. J., Knipe D. M. Transcriptional control of herpesvirus gene expression: gene functions required for positive and negative regulation. Proc Natl Acad Sci U S A. 1986 Jan;83(2):256–260. doi: 10.1073/pnas.83.2.256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gu B., Kuddus R., DeLuca N. A. Repression of activator-mediated transcription by herpes simplex virus ICP4 via a mechanism involving interactions with the basal transcription factors TATA-binding protein and TFIIB. Mol Cell Biol. 1995 Jul;15(7):3618–3626. doi: 10.1128/mcb.15.7.3618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hardwicke M. A., Sandri-Goldin R. M. The herpes simplex virus regulatory protein ICP27 contributes to the decrease in cellular mRNA levels during infection. J Virol. 1994 Aug;68(8):4797–4810. doi: 10.1128/jvi.68.8.4797-4810.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hardy W. R., Sandri-Goldin R. M. Herpes simplex virus inhibits host cell splicing, and regulatory protein ICP27 is required for this effect. J Virol. 1994 Dec;68(12):7790–7799. doi: 10.1128/jvi.68.12.7790-7799.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hay J., Koteles G. J., Keir H. M., Subak Sharpe H. Herpes virus specified ribonucleic acids. Nature. 1966 Apr 23;210(5034):387–390. doi: 10.1038/210387b0. [DOI] [PubMed] [Google Scholar]
  19. Jones F. E., Smibert C. A., Smiley J. R. Mutational analysis of the herpes simplex virus virion host shutoff protein: evidence that vhs functions in the absence of other viral proteins. J Virol. 1995 Aug;69(8):4863–4871. doi: 10.1128/jvi.69.8.4863-4871.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kanangat S., Babu J. S., Knipe D. M., Rouse B. T. HSV-1-mediated modulation of cytokine gene expression in a permissive cell line: selective upregulation of IL-6 gene expression. Virology. 1996 May 1;219(1):295–300. doi: 10.1006/viro.1996.0250. [DOI] [PubMed] [Google Scholar]
  21. Kemp L. M., Latchman D. S. Induction and repression of cellular gene transcription during herpes simplex virus infection are mediated by different viral immediate-early gene products. Eur J Biochem. 1988 Jun 1;174(2):443–449. doi: 10.1111/j.1432-1033.1988.tb14118.x. [DOI] [PubMed] [Google Scholar]
  22. Kemp L. M., Latchman D. S. The herpes simplex virus type 1 immediate-early protein ICP4 specifically induces increased transcription of the human ubiquitin B gene without affecting the ubiquitin A and C genes. Virology. 1988 Sep;166(1):258–261. doi: 10.1016/0042-6822(88)90170-5. [DOI] [PubMed] [Google Scholar]
  23. Krumm A., Hickey L. B., Groudine M. Promoter-proximal pausing of RNA polymerase II defines a general rate-limiting step after transcription initiation. Genes Dev. 1995 Mar 1;9(5):559–572. doi: 10.1101/gad.9.5.559. [DOI] [PubMed] [Google Scholar]
  24. Krumm A., Meulia T., Brunvand M., Groudine M. The block to transcriptional elongation within the human c-myc gene is determined in the promoter-proximal region. Genes Dev. 1992 Nov;6(11):2201–2213. doi: 10.1101/gad.6.11.2201. [DOI] [PubMed] [Google Scholar]
  25. Laybourn P. J., Dahmus M. E. Phosphorylation of RNA polymerase IIA occurs subsequent to interaction with the promoter and before the initiation of transcription. J Biol Chem. 1990 Aug 5;265(22):13165–13173. [PubMed] [Google Scholar]
  26. Leys E. J., Crouse G. F., Kellems R. E. Dihydrofolate reductase gene expression in cultured mouse cells is regulated by transcript stabilization in the nucleus. J Cell Biol. 1984 Jul;99(1 Pt 1):180–187. doi: 10.1083/jcb.99.1.180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Mayman B. A., Nishioka Y. Differential stability of host mRNAs in Friend erythroleukemia cells infected with herpes simplex virus type 1. J Virol. 1985 Jan;53(1):1–6. doi: 10.1128/jvi.53.1.1-6.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. McLauchlan J., Phelan A., Loney C., Sandri-Goldin R. M., Clements J. B. Herpes simplex virus IE63 acts at the posttranscriptional level to stimulate viral mRNA 3' processing. J Virol. 1992 Dec;66(12):6939–6945. doi: 10.1128/jvi.66.12.6939-6945.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mears W. E., Lam V., Rice S. A. Identification of nuclear and nucleolar localization signals in the herpes simplex virus regulatory protein ICP27. J Virol. 1995 Feb;69(2):935–947. doi: 10.1128/jvi.69.2.935-947.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. O'Hare P., Hayward G. S. Three trans-acting regulatory proteins of herpes simplex virus modulate immediate-early gene expression in a pathway involving positive and negative feedback regulation. J Virol. 1985 Dec;56(3):723–733. doi: 10.1128/jvi.56.3.723-733.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Panning B., Smiley J. R. Regulation of cellular genes transduced by herpes simplex virus. J Virol. 1989 May;63(5):1929–1937. doi: 10.1128/jvi.63.5.1929-1937.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Payne J. M., Dahmus M. E. Partial purification and characterization of two distinct protein kinases that differentially phosphorylate the carboxyl-terminal domain of RNA polymerase subunit IIa. J Biol Chem. 1993 Jan 5;268(1):80–87. [PubMed] [Google Scholar]
  33. Phelan A., Carmo-Fonseca M., McLaughlan J., Lamond A. I., Clements J. B. A herpes simplex virus type 1 immediate-early gene product, IE63, regulates small nuclear ribonucleoprotein distribution. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9056–9060. doi: 10.1073/pnas.90.19.9056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Pizer L. I., Beard P. The effect of herpes virus infection on mRNA in polyoma virus transformed cells. Virology. 1976 Dec;75(2):477–480. doi: 10.1016/0042-6822(76)90045-3. [DOI] [PubMed] [Google Scholar]
  35. Poffenberger K. L., Raichlen P. E., Herman R. C. In vitro characterization of a herpes simplex virus type 1 ICP22 deletion mutant. Virus Genes. 1993 Jun;7(2):171–186. doi: 10.1007/BF01702397. [DOI] [PubMed] [Google Scholar]
  36. Preston C. M., Newton A. A. The effects of herpes simplex virus type 1 on cellular DNA-dependent RNA polymerase activities. J Gen Virol. 1976 Dec;33(3):471–482. doi: 10.1099/0022-1317-33-3-471. [DOI] [PubMed] [Google Scholar]
  37. Preston V. G. Herpes simplex virus activates expression of a cellular gene by specific binding to the cell surface. Virology. 1990 Jun;176(2):474–482. doi: 10.1016/0042-6822(90)90017-l. [DOI] [PubMed] [Google Scholar]
  38. Rice S. A., Knipe D. M. Genetic evidence for two distinct transactivation functions of the herpes simplex virus alpha protein ICP27. J Virol. 1990 Apr;64(4):1704–1715. doi: 10.1128/jvi.64.4.1704-1715.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rice S. A., Long M. C., Lam V., Schaffer P. A., Spencer C. A. Herpes simplex virus immediate-early protein ICP22 is required for viral modification of host RNA polymerase II and establishment of the normal viral transcription program. J Virol. 1995 Sep;69(9):5550–5559. doi: 10.1128/jvi.69.9.5550-5559.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Rice S. A., Long M. C., Lam V., Spencer C. A. RNA polymerase II is aberrantly phosphorylated and localized to viral replication compartments following herpes simplex virus infection. J Virol. 1994 Feb;68(2):988–1001. doi: 10.1128/jvi.68.2.988-1001.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Rougvie A. E., Lis J. T. The RNA polymerase II molecule at the 5' end of the uninduced hsp70 gene of D. melanogaster is transcriptionally engaged. Cell. 1988 Sep 9;54(6):795–804. doi: 10.1016/s0092-8674(88)91087-2. [DOI] [PubMed] [Google Scholar]
  42. Sacks W. R., Greene C. C., Aschman D. P., Schaffer P. A. Herpes simplex virus type 1 ICP27 is an essential regulatory protein. J Virol. 1985 Sep;55(3):796–805. doi: 10.1128/jvi.55.3.796-805.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sears A. E., Halliburton I. W., Meignier B., Silver S., Roizman B. Herpes simplex virus 1 mutant deleted in the alpha 22 gene: growth and gene expression in permissive and restrictive cells and establishment of latency in mice. J Virol. 1985 Aug;55(2):338–346. doi: 10.1128/jvi.55.2.338-346.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Smibert C. A., Smiley J. R. Differential regulation of endogenous and transduced beta-globin genes during infection of erythroid cells with a herpes simplex virus type 1 recombinant. J Virol. 1990 Aug;64(8):3882–3894. doi: 10.1128/jvi.64.8.3882-3894.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Smiley J. R., Smibert C., Everett R. D. Expression of a cellular gene cloned in herpes simplex virus: rabbit beta-globin is regulated as an early viral gene in infected fibroblasts. J Virol. 1987 Aug;61(8):2368–2377. doi: 10.1128/jvi.61.8.2368-2377.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Smith C. A., Bates P., Rivera-Gonzalez R., Gu B., DeLuca N. A. ICP4, the major transcriptional regulatory protein of herpes simplex virus type 1, forms a tripartite complex with TATA-binding protein and TFIIB. J Virol. 1993 Aug;67(8):4676–4687. doi: 10.1128/jvi.67.8.4676-4687.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Spencer C. A., Kilvert M. A. Transcription elongation in the human c-myc gene is governed by overall transcription initiation levels in Xenopus oocytes. Mol Cell Biol. 1993 Feb;13(2):1296–1305. doi: 10.1128/mcb.13.2.1296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Spencer C. A., LeStrange R. C., Novak U., Hayward W. S., Groudine M. The block to transcription elongation is promoter dependent in normal and Burkitt's lymphoma c-myc alleles. Genes Dev. 1990 Jan;4(1):75–88. doi: 10.1101/gad.4.1.75. [DOI] [PubMed] [Google Scholar]
  49. Stenberg R. M., Pizer L. I. Herpes simplex virus-induced changes in cellular and adenovirus RNA metabolism in an adenovirus type 5-transformed human cell line. J Virol. 1982 May;42(2):474–487. doi: 10.1128/jvi.42.2.474-487.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Sussman D. J., Chung J., Leder P. In vitro and in vivo analysis of the c-myc RNA polymerase III promoter. Nucleic Acids Res. 1991 Sep 25;19(18):5045–5052. doi: 10.1093/nar/19.18.5045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wagner E. K., Roizman B. Ribonucleic acid synthesis in cells infected with herpes simplex virus. I. Patterns of ribonucleic acid synthesis in productively infected cells. J Virol. 1969 Jul;4(1):36–46. doi: 10.1128/jvi.4.1.36-46.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES