Linked Life Data

20976203

Source:http://linkedlifedata.com/resource/pubmed/id/20976203

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2010-10-26
pubmed:abstractText
The human immunodeficiency virus 1 (HIV-1) transcriptional transactivator (Tat) is essential for synthesis of full-length transcripts from the integrated viral genome by RNA polymerase II (Pol II). Tat recruits the host positive transcription elongation factor b (P-TEFb) to the HIV-1 promoter through binding to the transactivator RNA (TAR) at the 5'-end of the nascent HIV transcript. P-TEFb is a general Pol II transcription factor; its cellular activity is controlled by the 7SK small nuclear RNA (snRNA) and the HEXIM1 protein, which sequester P-TEFb into transcriptionally inactive 7SK/HEXIM/P-TEFb snRNP. Besides targeting P-TEFb to HIV transcription, Tat also increases the nuclear level of active P-TEFb through promoting its dissociation from the 7SK/HEXIM/P-TEFb RNP by an unclear mechanism. In this study, by using in vitro and in vivo RNA-protein binding assays, we demonstrate that HIV-1 Tat binds with high specificity and efficiency to an evolutionarily highly conserved stem-bulge-stem motif of the 5'-hairpin of human 7SK snRNA. The newly discovered Tat-binding motif of 7SK is structurally and functionally indistinguishable from the extensively characterized Tat-binding site of HIV TAR and importantly, it is imbedded in the HEXIM-binding elements of 7SK snRNA. We show that Tat efficiently replaces HEXIM1 on the 7SK snRNA in vivo and therefore, it promotes the disassembly of the 7SK/HEXIM/P-TEFb negative transcriptional regulatory snRNP to augment the nuclear level of active P-TEFb. This is the first demonstration that HIV-1 specifically targets an important cellular regulatory RNA, most probably to promote viral transcription and replication. Demonstration that the human 7SK snRNA carries a TAR RNA-like Tat-binding element that is essential for the normal transcriptional regulatory function of 7SK questions the viability of HIV therapeutic approaches based on small drugs blocking the Tat-binding site of HIV TAR.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
1553-7374
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
6
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
e1001152
pubmed:meshHeading
pubmed-meshheading:20976203-5' Flanking Region, pubmed-meshheading:20976203-Base Sequence, pubmed-meshheading:20976203-Binding Sites, pubmed-meshheading:20976203-Cells, Cultured, pubmed-meshheading:20976203-Gene Expression Regulation, Viral, pubmed-meshheading:20976203-HIV-1, pubmed-meshheading:20976203-HeLa Cells, pubmed-meshheading:20976203-Humans, pubmed-meshheading:20976203-Models, Biological, pubmed-meshheading:20976203-Molecular Sequence Data, pubmed-meshheading:20976203-Nucleic Acid Conformation, pubmed-meshheading:20976203-Positive Transcriptional Elongation Factor B, pubmed-meshheading:20976203-Protein Binding, pubmed-meshheading:20976203-Protein Multimerization, pubmed-meshheading:20976203-RNA, Small Nuclear, pubmed-meshheading:20976203-RNA-Binding Proteins, pubmed-meshheading:20976203-Transcriptional Activation, pubmed-meshheading:20976203-tat Gene Products, Human Immunodeficiency Virus
pubmed:year
2010
pubmed:articleTitle
Controlling cellular P-TEFb activity by the HIV-1 transcriptional transactivator Tat.
pubmed:affiliation
Laboratoire de Biologie Moléculaire Eucaryote du CNRS, UMR5099, IFR109 CNRS, Université Paul Sabatier, Toulouse, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't