Abstract
A novel family of transcripts that span the junction between the long and short segments of the herpes simplex virus type 1 genome has been identified. These transcripts, designated L/S junction-spanning transcripts (L/STs), are synthesized in abundance in a variety of cells infected with mutant viruses defective in the gene for ICP4, the major transcriptional regulatory protein of the virus. Transcription of abundant 2.3- and 8.5-kb series of L/STs was shown to initiate within the same sequences as less abundant 4.2-, 7.3-, and > 9.5-kb transcripts by Northern (RNA) blot analysis. S1 nuclease analysis revealed a single 5' terminus 28 bp downstream of a TATA box and 6 bp downstream of a consensus ICP4 binding site. The location of the transcriptional start site indicates that the promoter of the L/STs likely corresponds to the bidirectional promoter described by Bohenzky et al. (R. A. Bohenzky, A. G. Papavassiliou, I. H. Gelman, and S. Silverstein, J. Virol. 67:632-642, 1993). The L/STs accumulate with late kinetics in ICP4 mutant-infected cells and are polyadenylated. Mutant viruses encoding forms of ICP4 unable to bind the consensus site, ATCGTC, exhibited abundant expression of the L/STs, whereas mutants encoding forms of ICP4 able to bind this site expressed no detectable L/STs, suggesting that ICP4 plays a critical role in repressing L/ST expression. Their synthesis in ICP4 mutant-infected cells is inhibited by the protein synthesis inhibitor cycloheximide, indicating that they are induced either by an immediate-early viral protein other than ICP4 or by a virus-induced cellular protein. Preliminary evidence indicates that the L/STs are not present in latently infected ganglia. The abundant expression of the L/STs with late kinetics only in the absence of functional ICP4 and the sensitivity of their synthesis to cycloheximide indicate that they are not members of any of the recognized kinetic classes of herpes simplex virus type 1 transcripts but constitute a new class of viral transcript.
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- Batchelor A. H., O'Hare P. Regulation and cell-type-specific activity of a promoter located upstream of the latency-associated transcript of herpes simplex virus type 1. J Virol. 1990 Jul;64(7):3269–3279. doi: 10.1128/jvi.64.7.3269-3279.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Batterson W., Roizman B. Characterization of the herpes simplex virion-associated factor responsible for the induction of alpha genes. J Virol. 1983 May;46(2):371–377. doi: 10.1128/jvi.46.2.371-377.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bohenzky R. A., Papavassiliou A. G., Gelman I. H., Silverstein S. Identification of a promoter mapping within the reiterated sequences that flank the herpes simplex virus type 1 UL region. J Virol. 1993 Feb;67(2):632–642. doi: 10.1128/jvi.67.2.632-642.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cai W. Z., Schaffer P. A. Herpes simplex virus type 1 ICP0 plays a critical role in the de novo synthesis of infectious virus following transfection of viral DNA. J Virol. 1989 Nov;63(11):4579–4589. doi: 10.1128/jvi.63.11.4579-4589.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cai W., Astor T. L., Liptak L. M., Cho C., Coen D. M., Schaffer P. A. The herpes simplex virus type 1 regulatory protein ICP0 enhances virus replication during acute infection and reactivation from latency. J Virol. 1993 Dec;67(12):7501–7512. doi: 10.1128/jvi.67.12.7501-7512.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cheung A. K. Cloning of the latency gene and the early protein 0 gene of pseudorabies virus. J Virol. 1991 Oct;65(10):5260–5271. doi: 10.1128/jvi.65.10.5260-5271.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chou J., Kern E. R., Whitley R. J., Roizman B. Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture. Science. 1990 Nov 30;250(4985):1262–1266. doi: 10.1126/science.2173860. [DOI] [PubMed] [Google Scholar]
- Chou J., Roizman B. The gamma 1(34.5) gene of herpes simplex virus 1 precludes neuroblastoma cells from triggering total shutoff of protein synthesis characteristic of programed cell death in neuronal cells. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3266–3270. doi: 10.1073/pnas.89.8.3266. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chou J., Roizman B. The terminal a sequence of the herpes simplex virus genome contains the promoter of a gene located in the repeat sequences of the L component. J Virol. 1986 Feb;57(2):629–637. doi: 10.1128/jvi.57.2.629-637.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Conner J., Cooper J., Furlong J., Clements J. B. An autophosphorylating but not transphosphorylating activity is associated with the unique N terminus of the herpes simplex virus type 1 ribonucleotide reductase large subunit. J Virol. 1992 Dec;66(12):7511–7516. doi: 10.1128/jvi.66.12.7511-7516.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Davison A. J., Wilkie N. M. Nucleotide sequences of the joint between the L and S segments of herpes simplex virus types 1 and 2. J Gen Virol. 1981 Aug;55(Pt 2):315–331. doi: 10.1099/0022-1317-55-2-315. [DOI] [PubMed] [Google Scholar]
- DeLuca N. A., Courtney M. A., Schaffer P. A. Temperature-sensitive mutants in herpes simplex virus type 1 ICP4 permissive for early gene expression. J Virol. 1984 Dec;52(3):767–776. doi: 10.1128/jvi.52.3.767-776.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- DeLuca N. A., McCarthy A. M., Schaffer P. A. Isolation and characterization of deletion mutants of herpes simplex virus type 1 in the gene encoding immediate-early regulatory protein ICP4. J Virol. 1985 Nov;56(2):558–570. doi: 10.1128/jvi.56.2.558-570.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- DeLuca N. A., Schaffer P. A. Activities of herpes simplex virus type 1 (HSV-1) ICP4 genes specifying nonsense peptides. Nucleic Acids Res. 1987 Jun 11;15(11):4491–4511. doi: 10.1093/nar/15.11.4491. [DOI] [PMC free article] [PubMed] [Google Scholar]
- DeLuca N. A., Schaffer P. A. Physical and functional domains of the herpes simplex virus transcriptional regulatory protein ICP4. J Virol. 1988 Mar;62(3):732–743. doi: 10.1128/jvi.62.3.732-743.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Deatly A. M., Spivack J. G., Lavi E., Fraser N. W. RNA from an immediate early region of the type 1 herpes simplex virus genome is present in the trigeminal ganglia of latently infected mice. Proc Natl Acad Sci U S A. 1987 May;84(10):3204–3208. doi: 10.1073/pnas.84.10.3204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Deatly A. M., Spivack J. G., Lavi E., O'Boyle D. R., 2nd, Fraser N. W. Latent herpes simplex virus type 1 transcripts in peripheral and central nervous system tissues of mice map to similar regions of the viral genome. J Virol. 1988 Mar;62(3):749–756. doi: 10.1128/jvi.62.3.749-756.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Deiss L. P., Chou J., Frenkel N. Functional domains within the a sequence involved in the cleavage-packaging of herpes simplex virus DNA. J Virol. 1986 Sep;59(3):605–618. doi: 10.1128/jvi.59.3.605-618.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Deiss L. P., Frenkel N. Herpes simplex virus amplicon: cleavage of concatemeric DNA is linked to packaging and involves amplification of the terminally reiterated a sequence. J Virol. 1986 Mar;57(3):933–941. doi: 10.1128/jvi.57.3.933-941.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Devi-Rao G. B., Goodart S. A., Hecht L. M., Rochford R., Rice M. K., Wagner E. K. Relationship between polyadenylated and nonpolyadenylated herpes simplex virus type 1 latency-associated transcripts. J Virol. 1991 May;65(5):2179–2190. doi: 10.1128/jvi.65.5.2179-2190.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- DiDonato J. A., Spitzner J. R., Muller M. T. A predictive model for DNA recognition by the herpes simplex virus protein ICP4. J Mol Biol. 1991 Jun 5;219(3):451–470. doi: 10.1016/0022-2836(91)90186-a. [DOI] [PubMed] [Google Scholar]
- Dixon R. A., Schaffer P. A. Fine-structure mapping and functional analysis of temperature-sensitive mutants in the gene encoding the herpes simplex virus type 1 immediate early protein VP175. J Virol. 1980 Oct;36(1):189–203. doi: 10.1128/jvi.36.1.189-203.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goding C. R., O'Hare P. Herpes simplex virus Vmw65-octamer binding protein interaction: a paradigm for combinatorial control of transcription. Virology. 1989 Dec;173(2):363–367. doi: 10.1016/0042-6822(89)90548-5. [DOI] [PubMed] [Google Scholar]
- Holland L. E., Anderson K. P., Shipman C., Jr, Wagner E. K. Viral DNA synthesis is required for the efficient expression of specific herpes simplex virus type 1 mRNA species. Virology. 1980 Feb;101(1):10–24. doi: 10.1016/0042-6822(80)90479-1. [DOI] [PubMed] [Google Scholar]
- Honess R. W., Roizman B. Regulation of herpesvirus macromolecular synthesis. I. Cascade regulation of the synthesis of three groups of viral proteins. J Virol. 1974 Jul;14(1):8–19. doi: 10.1128/jvi.14.1.8-19.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Honess R. W., Roizman B. Regulation of herpesvirus macromolecular synthesis: sequential transition of polypeptide synthesis requires functional viral polypeptides. Proc Natl Acad Sci U S A. 1975 Apr;72(4):1276–1280. doi: 10.1073/pnas.72.4.1276. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Imbalzano A. N., Coen D. M., DeLuca N. A. Herpes simplex virus transactivator ICP4 operationally substitutes for the cellular transcription factor Sp1 for efficient expression of the viral thymidine kinase gene. J Virol. 1991 Feb;65(2):565–574. doi: 10.1128/jvi.65.2.565-574.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Imbalzano A. N., Shepard A. A., DeLuca N. A. Functional relevance of specific interactions between herpes simplex virus type 1 ICP4 and sequences from the promoter-regulatory domain of the viral thymidine kinase gene. J Virol. 1990 Jun;64(6):2620–2631. doi: 10.1128/jvi.64.6.2620-2631.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jones N. C., Rigby P. W., Ziff E. B. Trans-acting protein factors and the regulation of eukaryotic transcription: lessons from studies on DNA tumor viruses. Genes Dev. 1988 Mar;2(3):267–281. doi: 10.1101/gad.2.3.267. [DOI] [PubMed] [Google Scholar]
- Jones P. C., Roizman B. Regulation of herpesvirus macromolecular synthesis. VIII. The transcription program consists of three phases during which both extent of transcription and accumulation of RNA in the cytoplasm are regulated. J Virol. 1979 Aug;31(2):299–314. doi: 10.1128/jvi.31.2.299-314.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Krause P. R., Croen K. D., Straus S. E., Ostrove J. M. Detection and preliminary characterization of herpes simplex virus type 1 transcripts in latently infected human trigeminal ganglia. J Virol. 1988 Dec;62(12):4819–4823. doi: 10.1128/jvi.62.12.4819-4823.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Leib D. A., Bogard C. L., Kosz-Vnenchak M., Hicks K. A., Coen D. M., Knipe D. M., Schaffer P. A. A deletion mutant of the latency-associated transcript of herpes simplex virus type 1 reactivates from the latent state with reduced frequency. J Virol. 1989 Jul;63(7):2893–2900. doi: 10.1128/jvi.63.7.2893-2900.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McCarthy A. M., McMahan L., Schaffer P. A. Herpes simplex virus type 1 ICP27 deletion mutants exhibit altered patterns of transcription and are DNA deficient. J Virol. 1989 Jan;63(1):18–27. doi: 10.1128/jvi.63.1.18-27.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McGeoch D. J., Dolan A., Donald S., Rixon F. J. Sequence determination and genetic content of the short unique region in the genome of herpes simplex virus type 1. J Mol Biol. 1985 Jan 5;181(1):1–13. doi: 10.1016/0022-2836(85)90320-1. [DOI] [PubMed] [Google Scholar]
- Mitchell W. J., Lirette R. P., Fraser N. W. Mapping of low abundance latency-associated RNA in the trigeminal ganglia of mice latently infected with herpes simplex virus type 1. J Gen Virol. 1990 Jan;71(Pt 1):125–132. doi: 10.1099/0022-1317-71-1-125. [DOI] [PubMed] [Google Scholar]
- Murchie M. J., McGeoch D. J. DNA sequence analysis of an immediate-early gene region of the herpes simplex virus type 1 genome (map coordinates 0.950 to 0.978). J Gen Virol. 1982 Sep;62(Pt 1):1–15. doi: 10.1099/0022-1317-62-1-1. [DOI] [PubMed] [Google Scholar]
- Nasseri M., Mocarski E. S. The cleavage recognition signal is contained within sequences surrounding an a-a junction in herpes simplex virus DNA. Virology. 1988 Nov;167(1):25–30. doi: 10.1016/0042-6822(88)90050-5. [DOI] [PubMed] [Google Scholar]
- 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]
- Rock D. L., Nesburn A. B., Ghiasi H., Ong J., Lewis T. L., Lokensgard J. R., Wechsler S. L. Detection of latency-related viral RNAs in trigeminal ganglia of rabbits latently infected with herpes simplex virus type 1. J Virol. 1987 Dec;61(12):3820–3826. doi: 10.1128/jvi.61.12.3820-3826.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Sacks W. R., Schaffer P. A. Deletion mutants in the gene encoding the herpes simplex virus type 1 immediate-early protein ICP0 exhibit impaired growth in cell culture. J Virol. 1987 Mar;61(3):829–839. doi: 10.1128/jvi.61.3.829-839.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sample J., Hummel M., Braun D., Birkenbach M., Kieff E. Nucleotide sequences of mRNAs encoding Epstein-Barr virus nuclear proteins: a probable transcriptional initiation site. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5096–5100. doi: 10.1073/pnas.83.14.5096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sandri-Goldin R. M., Levine M., Glorioso J. C. Method for induction of mutations in physically defined regions of the herpes simplex virus genome. J Virol. 1981 Apr;38(1):41–49. doi: 10.1128/jvi.38.1.41-49.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schaffer P. A., Carter V. C., Timbury M. C. Collaborative complementation study of temperature-sensitive mutants of herpes simplex virus types 1 and 2. J Virol. 1978 Sep;27(3):490–504. doi: 10.1128/jvi.27.3.490-504.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Smiley J. R., Duncan J., Howes M. Sequence requirements for DNA rearrangements induced by the terminal repeat of herpes simplex virus type 1 KOS DNA. J Virol. 1990 Oct;64(10):5036–5050. doi: 10.1128/jvi.64.10.5036-5050.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Smiley J. R., Lavery C., Howes M. The herpes simplex virus type 1 (HSV-1) a sequence serves as a cleavage/packaging signal but does not drive recombinational genome isomerization when it is inserted into the HSV-2 genome. J Virol. 1992 Dec;66(12):7505–7510. doi: 10.1128/jvi.66.12.7505-7510.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Spaete R. R., Frenkel N. The herpes simplex virus amplicon: a new eucaryotic defective-virus cloning-amplifying vector. Cell. 1982 Aug;30(1):295–304. doi: 10.1016/0092-8674(82)90035-6. [DOI] [PubMed] [Google Scholar]
- Spivack J. G., Fraser N. W. Expression of herpes simplex virus type 1 latency-associated transcripts in the trigeminal ganglia of mice during acute infection and reactivation of latent infection. J Virol. 1988 May;62(5):1479–1485. doi: 10.1128/jvi.62.5.1479-1485.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stevens J. G., Wagner E. K., Devi-Rao G. B., Cook M. L., Feldman L. T. RNA complementary to a herpesvirus alpha gene mRNA is prominent in latently infected neurons. Science. 1987 Feb 27;235(4792):1056–1059. doi: 10.1126/science.2434993. [DOI] [PubMed] [Google Scholar]
- Stow N. D. Localization of an origin of DNA replication within the TRS/IRS repeated region of the herpes simplex virus type 1 genome. EMBO J. 1982;1(7):863–867. doi: 10.1002/j.1460-2075.1982.tb01261.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stow N. D., McMonagle E. C. Characterization of the TRS/IRS origin of DNA replication of herpes simplex virus type 1. Virology. 1983 Oct 30;130(2):427–438. doi: 10.1016/0042-6822(83)90097-1. [DOI] [PubMed] [Google Scholar]
- Varmuza S. L., Smiley J. R. Signals for site-specific cleavage of HSV DNA: maturation involves two separate cleavage events at sites distal to the recognition sequences. Cell. 1985 Jul;41(3):793–802. doi: 10.1016/s0092-8674(85)80060-x. [DOI] [PubMed] [Google Scholar]
- Vlazny D. A., Kwong A., Frenkel N. Site-specific cleavage/packaging of herpes simplex virus DNA and the selective maturation of nucleocapsids containing full-length viral DNA. Proc Natl Acad Sci U S A. 1982 Mar;79(5):1423–1427. doi: 10.1073/pnas.79.5.1423. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wagner E. K., Flanagan W. M., Devi-Rao G., Zhang Y. F., Hill J. M., Anderson K. P., Stevens J. G. The herpes simplex virus latency-associated transcript is spliced during the latent phase of infection. J Virol. 1988 Dec;62(12):4577–4585. doi: 10.1128/jvi.62.12.4577-4585.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weinheimer S. P., McKnight S. L. Transcriptional and post-transcriptional controls establish the cascade of herpes simplex virus protein synthesis. J Mol Biol. 1987 Jun 20;195(4):819–833. doi: 10.1016/0022-2836(87)90487-6. [DOI] [PubMed] [Google Scholar]
- Weller S. K., Lee K. J., Sabourin D. J., Schaffer P. A. Genetic analysis of temperature-sensitive mutants which define the gene for the major herpes simplex virus type 1 DNA-binding protein. J Virol. 1983 Jan;45(1):354–366. doi: 10.1128/jvi.45.1.354-366.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]