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. 1996 May 15;24(10):1895–1900. doi: 10.1093/nar/24.10.1895

A nuclear matrix-specific factor that binds a specific segment of the negative regulatory element (NRE) of HIV-1 LTR and inhibits NF-kappa(B) activity.

T Hoover 1, J Mikovits 1, D Court 1, Y L Liu 1, H F Kung 1, Raziuddin 1
PMCID: PMC145884  PMID: 8657571

Abstract

The negative regulatory element (NRE) of human immunodeficiency virus type-1 (HIV-1) long terminal repeat (LTR) is a defined region that has been reported to downregulate LTR-directed HIV gene expression. However, information on the precise role of this region in regulating HIV gone transcription is lacking. We have investigated the possibility that these NRE sequences regulate HIV transcription by a mechanism mediated through a nuclear matrix-specific DNA-protein interaction. We find a nuclear matrix attachment region (MAR) present within the NRE of the HIV-1 LTR that recognizes a sequence-specific DNA-binding protein present in the nuclear matrix of HIV infected cells. Moreover, we also show that the purified DNA-binding nuclear matrix protein (NMP) specifically represses the DNA-binding activity of NF-kappaB. It is likely that the MAR and MAR-enriched specific DNA-binding NMP are brought into juxtaposition by the non-chromatin scaffolding of the nucleus, thus influencing NF-kappaB (and other nuclear proteins) DNA-binding activity through protein-protein and protein-DNA interactions. Our date suggest that one possible role of the NRE could be to act as a matrix attachment site in the nuclear matrix, thus, allowing interaction with a sequence-specific trans-acting factor. The negative effect on NF-kappaB activity due to this MAR-NMP-specific interaction provides a mechanism by which the NRE downregulates HIV gene expression.

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Selected References

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  1. Amati B. B., Gasser S. M. Chromosomal ARS and CEN elements bind specifically to the yeast nuclear scaffold. Cell. 1988 Sep 23;54(7):967–978. doi: 10.1016/0092-8674(88)90111-0. [DOI] [PubMed] [Google Scholar]
  2. Bachelerie F., Alcami J., Arenzana-Seisdedos F., Virelizier J. L. HIV enhancer activity perpetuated by NF-kappa B induction on infection of monocytes. Nature. 1991 Apr 25;350(6320):709–712. doi: 10.1038/350709a0. [DOI] [PubMed] [Google Scholar]
  3. Baeuerle P. A., Baltimore D. I kappa B: a specific inhibitor of the NF-kappa B transcription factor. Science. 1988 Oct 28;242(4878):540–546. doi: 10.1126/science.3140380. [DOI] [PubMed] [Google Scholar]
  4. Bidwell J. P., Van Wijnen A. J., Fey E. G., Dworetzky S., Penman S., Stein J. L., Lian J. B., Stein G. S. Osteocalcin gene promoter-binding factors are tissue-specific nuclear matrix components. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3162–3166. doi: 10.1073/pnas.90.8.3162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Böhnlein E., Lowenthal J. W., Siekevitz M., Ballard D. W., Franza B. R., Greene W. C. The same inducible nuclear proteins regulates mitogen activation of both the interleukin-2 receptor-alpha gene and type 1 HIV. Cell. 1988 Jun 3;53(5):827–836. doi: 10.1016/0092-8674(88)90099-2. [DOI] [PubMed] [Google Scholar]
  6. Calvert I., Peng Z. Q., Kung H. F., Raziuddin Cloning and characterization of a novel sequence-specific DNA-binding protein recognizing the negative regulatory element (NRE) region of the HIV-1 long terminal repeat. Gene. 1991 May 30;101(2):171–176. doi: 10.1016/0378-1119(91)90408-4. [DOI] [PubMed] [Google Scholar]
  7. Cockerill P. N., Garrard W. T. Chromosomal loop anchorage of the kappa immunoglobulin gene occurs next to the enhancer in a region containing topoisomerase II sites. Cell. 1986 Jan 31;44(2):273–282. doi: 10.1016/0092-8674(86)90761-0. [DOI] [PubMed] [Google Scholar]
  8. Cullen B. R. Trans-activation of human immunodeficiency virus occurs via a bimodal mechanism. Cell. 1986 Sep 26;46(7):973–982. doi: 10.1016/0092-8674(86)90696-3. [DOI] [PubMed] [Google Scholar]
  9. Dworetzky S. I., Wright K. L., Fey E. G., Penman S., Lian J. B., Stein J. L., Stein G. S. Sequence-specific DNA-binding proteins are components of a nuclear matrix-attachment site. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4178–4182. doi: 10.1073/pnas.89.9.4178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Feinberg M. B., Jarrett R. F., Aldovini A., Gallo R. C., Wong-Staal F. HTLV-III expression and production involve complex regulation at the levels of splicing and translation of viral RNA. Cell. 1986 Sep 12;46(6):807–817. doi: 10.1016/0092-8674(86)90062-0. [DOI] [PubMed] [Google Scholar]
  11. Fey E. G., Penman S. Nuclear matrix proteins reflect cell type of origin in cultured human cells. Proc Natl Acad Sci U S A. 1988 Jan;85(1):121–125. doi: 10.1073/pnas.85.1.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Folks T., Powell D. M., Lightfoote M. M., Benn S., Martin M. A., Fauci A. S. Induction of HTLV-III/LAV from a nonvirus-producing T-cell line: implications for latency. Science. 1986 Feb 7;231(4738):600–602. doi: 10.1126/science.3003906. [DOI] [PubMed] [Google Scholar]
  13. Garcia J. A., Wu F. K., Mitsuyasu R., Gaynor R. B. Interactions of cellular proteins involved in the transcriptional regulation of the human immunodeficiency virus. EMBO J. 1987 Dec 1;6(12):3761–3770. doi: 10.1002/j.1460-2075.1987.tb02711.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gasser S. M., Laemmli U. K. Cohabitation of scaffold binding regions with upstream/enhancer elements of three developmentally regulated genes of D. melanogaster. Cell. 1986 Aug 15;46(4):521–530. doi: 10.1016/0092-8674(86)90877-9. [DOI] [PubMed] [Google Scholar]
  15. Griffin G. E., Leung K., Folks T. M., Kunkel S., Nabel G. J. Activation of HIV gene expression during monocyte differentiation by induction of NF-kappa B. Nature. 1989 May 4;339(6219):70–73. doi: 10.1038/339070a0. [DOI] [PubMed] [Google Scholar]
  16. Howard M. T., Griffith J. D. A cluster of strong topoisomerase II cleavage sites is located near an integrated human immunodeficiency virus. J Mol Biol. 1993 Aug 20;232(4):1060–1068. doi: 10.1006/jmbi.1993.1460. [DOI] [PubMed] [Google Scholar]
  17. Izaurralde E., Mirkovitch J., Laemmli U. K. Interaction of DNA with nuclear scaffolds in vitro. J Mol Biol. 1988 Mar 5;200(1):111–125. doi: 10.1016/0022-2836(88)90337-3. [DOI] [PubMed] [Google Scholar]
  18. Jones K. A., Kadonaga J. T., Luciw P. A., Tjian R. Activation of the AIDS retrovirus promoter by the cellular transcription factor, Sp1. Science. 1986 May 9;232(4751):755–759. doi: 10.1126/science.3008338. [DOI] [PubMed] [Google Scholar]
  19. Lenardo M., Pierce J. W., Baltimore D. Protein-binding sites in Ig gene enhancers determine transcriptional activity and inducibility. Science. 1987 Jun 19;236(4808):1573–1577. doi: 10.1126/science.3109035. [DOI] [PubMed] [Google Scholar]
  20. Ludérus M. E., de Graaf A., Mattia E., den Blaauwen J. L., Grande M. A., de Jong L., van Driel R. Binding of matrix attachment regions to lamin B1. Cell. 1992 Sep 18;70(6):949–959. doi: 10.1016/0092-8674(92)90245-8. [DOI] [PubMed] [Google Scholar]
  21. Marciniak R. A., Garcia-Blanco M. A., Sharp P. A. Identification and characterization of a HeLa nuclear protein that specifically binds to the trans-activation-response (TAR) element of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1990 May;87(9):3624–3628. doi: 10.1073/pnas.87.9.3624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mikovits J. A., Raziuddin, Gonda M., Ruta M., Lohrey N. C., Kung H. F., Ruscetti F. W. Negative regulation of human immune deficiency virus replication in monocytes. Distinctions between restricted and latent expression in THP-1 cells. J Exp Med. 1990 May 1;171(5):1705–1720. doi: 10.1084/jem.171.5.1705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mirkovitch J., Mirault M. E., Laemmli U. K. Organization of the higher-order chromatin loop: specific DNA attachment sites on nuclear scaffold. Cell. 1984 Nov;39(1):223–232. doi: 10.1016/0092-8674(84)90208-3. [DOI] [PubMed] [Google Scholar]
  24. Nabel G., Baltimore D. An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987 Apr 16;326(6114):711–713. doi: 10.1038/326711a0. [DOI] [PubMed] [Google Scholar]
  25. Raziuddin, Mikovits J. A., Calvert I., Ghosh S., Kung H. F., Ruscetti F. W. Negative regulation of human immunodeficiency virus type 1 expression in monocytes: role of the 65-kDa plus 50-kDa NF-kappa B dimer. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9426–9430. doi: 10.1073/pnas.88.21.9426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rivière Y., Blank V., Kourilsky P., Israël A. Processing of the precursor of NF-kappa B by the HIV-1 protease during acute infection. Nature. 1991 Apr 18;350(6319):625–626. doi: 10.1038/350625a0. [DOI] [PubMed] [Google Scholar]
  27. Rosen C. A., Sodroski J. G., Haseltine W. A. The location of cis-acting regulatory sequences in the human T cell lymphotropic virus type III (HTLV-III/LAV) long terminal repeat. Cell. 1985 Jul;41(3):813–823. doi: 10.1016/s0092-8674(85)80062-3. [DOI] [PubMed] [Google Scholar]
  28. Rosen C. A., Terwilliger E., Dayton A., Sodroski J. G., Haseltine W. A. Intragenic cis-acting art gene-responsive sequences of the human immunodeficiency virus. Proc Natl Acad Sci U S A. 1988 Apr;85(7):2071–2075. doi: 10.1073/pnas.85.7.2071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sperry A. O., Blasquez V. C., Garrard W. T. Dysfunction of chromosomal loop attachment sites: illegitimate recombination linked to matrix association regions and topoisomerase II. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5497–5501. doi: 10.1073/pnas.86.14.5497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Stief A., Winter D. M., Strätling W. H., Sippel A. E. A nuclear DNA attachment element mediates elevated and position-independent gene activity. Nature. 1989 Sep 28;341(6240):343–345. doi: 10.1038/341343a0. [DOI] [PubMed] [Google Scholar]
  31. Tsutsui K., Tsutsui K., Okada S., Watarai S., Seki S., Yasuda T., Shohmori T. Identification and characterization of a nuclear scaffold protein that binds the matrix attachment region DNA. J Biol Chem. 1993 Jun 15;268(17):12886–12894. [PubMed] [Google Scholar]
  32. West M., Mikovits J., Princler G., Liu Y. L., Ruscetti F. W., Kung H. F., Raziuddin Characterization and purification of a novel transcriptional repressor from HeLa cell nuclear extracts recognizing the negative regulatory element region of human immunodeficiency virus-1 long terminal repeat. J Biol Chem. 1992 Dec 15;267(35):24948–24952. [PubMed] [Google Scholar]
  33. Zabel U., Baeuerle P. A. Purified human I kappa B can rapidly dissociate the complex of the NF-kappa B transcription factor with its cognate DNA. Cell. 1990 Apr 20;61(2):255–265. doi: 10.1016/0092-8674(90)90806-p. [DOI] [PubMed] [Google Scholar]
  34. von Kries J. P., Buhrmester H., Strätling W. H. A matrix/scaffold attachment region binding protein: identification, purification, and mode of binding. Cell. 1991 Jan 11;64(1):123–135. doi: 10.1016/0092-8674(91)90214-j. [DOI] [PubMed] [Google Scholar]

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