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• W2093897373 endingPage "e1001152" @default.
• W2093897373 startingPage "e1001152" @default.
• W2093897373 abstract "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." @default.
• W2093897373 created "2016-06-24" @default.
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• W2093897373 creator A5090669378 @default.
• W2093897373 date "2010-10-14" @default.
• W2093897373 modified "2023-10-10" @default.
• W2093897373 title "Controlling Cellular P-TEFb Activity by the HIV-1 Transcriptional Transactivator Tat" @default.
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• W2093897373 doi "https://doi.org/10.1371/journal.ppat.1001152" @default.
• W2093897373 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2954905" @default.
• W2093897373 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/20976203" @default.
• W2093897373 hasPublicationYear "2010" @default.
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