title: HMGA1 directly interacts with TAR to modulate basal and Tat-dependent HIV transcription.
abstract: The transactivating response element (TAR) of human immunodeficiency virus 1 (HIV-1) is essential for promoter transactivation by the viral transactivator of transcription (Tat). The Tat-TAR interaction thereby recruits active positive transcription elongation factor b (P-TEFb) from its inactive, 7SK/HEXIM1-bound form, leading to efficient viral transcription. Here, we show that the 7SK RNA-associating chromatin regulator HMGA1 can specifically bind to the HIV-1 TAR element and that 7SK RNA can thereby compete with TAR. The HMGA1-binding interface of TAR is located within the binding site for Tat and other cellular activators, and we further provide evidence for competition between HMGA1 and Tat for TAR-binding. HMGA1 negatively influences the expression of a HIV-1 promoter-driven reporter in a TAR-dependent manner, both in the presence and in the absence of Tat. The overexpression of the HMGA1-binding substructure of 7SK RNA results in a TAR-dependent gain of HIV-1 promoter activity similar to the effect of the shRNA-mediated knockdown of HMGA1. Our results support a model in which the HMGA1/TAR interaction prevents the binding of transcription-activating cellular co-factors and Tat, subsequently leading to reduced HIV-1 transcription.
authors: Institut des Hautes Études Scientifiques - Centre National de la Recherche Scientifique; Bures sur Yvette; France & Vaccine Research Institute; Institut Mondor de Recherche Biomédicale; Créteil, France.
authors: Sebastian
authors: S
authors: Eilebrecht
authors: Emmanuelle
authors: E
authors: Wilhelm
authors: Bernd-Joachim
authors: BJ
authors: Benecke
authors: Brendan
authors: B
authors: Bell
authors: Arndt G
authors: AG
authors: Benecke
mesh_terms: D001665:Binding Sites; D015967:Gene Expression Regulation, Viral; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D015658:HIV Infections / Q000378:metabolism / Q000821:virology; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism; D025741:HMGA1a Protein / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008957:Models, Genetic; D009690:Nucleic Acid Conformation; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D012367:RNA, Viral; D054322:tat Gene Products, Human Immunodeficiency Virus; D025741:HMGA1a Protein; D042925:Positive Transcriptional Elongation Factor B
keywords: 7SK snRNA; HIV-1; HMGA1; P-TEFb; TAR; Tat; elongation; transcription
references: Mol Cell. 2005 Aug 19;19(4):535-45
references: 16109377
references: Cell Biosci. 2011 Feb 25;1(1):9
references: 21711701
references: Cell. 2012 Sep 14;150(6):1147-57
references: 22980978
references: J Virol. 1995 Mar;69(3):1612-20
references: 7853496
references: J Biol Chem. 1999 Jul 16;274(29):20235-43
references: 10400641
references: Mol Cell Biol. 2003 Apr;23(8):2720-32
references: 12665574
references: J Virol. 2011 Dec;85(23):12614-21
references: 21937648
references: Nature. 2001 Nov 15;414(6861):317-22
references: 11713532
references: Mol Cell Biol. 2000 Jul;20(13):4666-79
references: 10848593
references: J Virol. 2000 Nov;74(22):10523-34
references: 11044097
references: J Biol Chem. 1995 May 26;270(21):12335-8
references: 7759473
references: Bioinformatics. 2010 Aug 15;26(16):2057-9
references: 20562414
references: Nucleic Acids Res. 1996 Feb 1;24(3):501-8
references: 8602364
references: J Virol. 2005 Jul;79(14):9180-91
references: 15994812
references: Science. 1991 Mar 29;251(5001):1597-600
references: 2011739
references: J Biol Chem. 1990 May 25;265(15):8573-82
references: 1692833
references: Nature. 1970 Aug 15;227(5259):680-5
references: 5432063
references: Cell. 2010 Apr 30;141(3):432-45
references: 20434984
references: J Virol. 2003 Jan;77(2):1598-603
references: 12502875
references: Nucleic Acids Res. 2000 Feb 1;28(3):663-8
references: 10637316
references: Mol Cell Biol. 2004 Jan;24(1):389-97
references: 14673171
references: Cell. 1998 Feb 20;92(4):451-62
references: 9491887
references: Methods Enzymol. 1989;180:262-88
references: 2482418
references: J Virol. 1989 Jun;63(6):2585-91
references: 2657100
references: J Biol Chem. 2001 Aug 24;276(34):31793-9
references: 11431468
references: Nature. 1987 Dec 3-9;330(6147):489-93
references: 2825027
references: Mol Cell. 2010 May 14;38(3):428-38
references: 20471948
references: RNA Biol. 2011 Nov-Dec;8(6):1084-93
references: 21957495
references: Gene. 1998 Mar 27;210(1):37-44
references: 9524214
references: Gene Expr. 1996;5(4-5):217-28
references: 8723388
references: Mol Cell. 2006 Aug 4;23(3):297-305
references: 16885020
references: Trends Biochem Sci. 2006 Feb;31(2):98-105
references: 16403635
references: Nat Struct Mol Biol. 2010 Jul;17(7):815-21
references: 20562857
references: Genes Dev. 1992 May;6(5):761-74
references: 1577271
references: J Biol Chem. 2003 Feb 14;278(7):4440-8
references: 12475984
references: PLoS Pathog. 2010 Oct 14;6(10):e1001152
references: 20976203
references: J Virol. 1989 Dec;63(12):5501-4
references: 2479775
references: Nucleic Acids Res. 2011 Mar;39(6):2057-72
references: 21087998
references: Retrovirology. 2012 Jul 26;9:62
references: 22834489
references: AIDS. 1992 Apr;6(4):347-63
references: 1616633
references: Mol Cell. 2005 Aug 19;19(4):523-34
references: 16109376
references: J Gen Virol. 1999 Oct;80 ( Pt 10):2629-2638
references: 10573156
references: Cell. 1997 Feb 21;88(4):483-92
references: 9038339
references: Biochem Biophys Res Commun. 2011 Mar 25;406(4):512-7
references: 21329653
references: Genes Dev. 1997 Oct 15;11(20):2633-44
references: 9334326
references: BMC Res Notes. 2008 Oct 28;1:100
references: 18957101
references: J Biol Chem. 2001 Feb 23;276(8):5445-51
references: 11096080
references: Nucleic Acids Res. 2007;35(13):4347-58
references: 17576689
references: Nature. 2001 Nov 15;414(6861):322-5
references: 11713533
references: Nucleic Acids Res. 2011 Apr;39(8):e52
references: 21297115
references: Mol Cell Biol. 1995 Mar;15(3):1786-96
references: 7862168
references: RNA. 2004 Mar;10(3):412-23
references: 14970387
references: J Biol Chem. 1996 Oct 25;271(43):27176-83
references: 8900211
references: J Cell Sci. 2004 Jul 15;117(Pt 16):3459-71
references: 15213251
references: Mol Cell. 2010 May 14;38(3):439-51
references: 20471949
references: Nat Commun. 2010 Oct 19;1:100
references: 20981028
references: Microbiol Mol Biol Rev. 2006 Sep;70(3):646-59
references: 16959964
references: Genes Dev. 1997 Oct 15;11(20):2622-32
references: 9334325
references: J Cell Physiol. 2001 Sep;188(3):352-8
references: 11473362