Inhibition of HIV-1 replication by P-TEFb inhibitors DRB, seliciclib and flavopiridol correlates with release of free P-TEFb from the large, inactive form of the complex

Biglione, Sebastian; Byers, Sarah A.; Price, John D.; Nguyen, Van Toan; Bensaude, Olivier; Price, David H.; Maury, Wendy

doi:10.1186/1742-4690-4-47

Cited by 116 publications

(118 citation statements)

References 54 publications

(76 reference statements)

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“…Further evidence indicating that AFF1 is a component of 7SK snRNP came from an experiment that examines the effect of the CDK9 inhibitor flavopiridol on 7SK snRNP formation. It has been shown previously that stress-inducing agents such as flavopiridol can disrupt the RNP to release P-TEFb for stress-induced gene expression (19,(21)(22)(23). As is consistent with AFF1 being an integral part of 7SK snRNP, treating HeLa cells with flavopiridol caused the dissociation of all HEXIM1 and most LARP7 from immunoprecipitated Flag-tagged AFF1 (AFF1-Flag) (Fig.…”

Section: Aff1 Interacts With 7sk Snrnp Components La Ribonucleoproteinsupporting

confidence: 71%

AFF1 is a ubiquitous P-TEFb partner to enable Tat extraction of P-TEFb from 7SK snRNP and formation of SECs for HIV transactivation

Xue

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The positive transcription elongation factor b (P-TEFb) stimulates RNA polymerase elongation by inducing the transition of promoter proximally paused polymerase II into a productively elongating state. P-TEFb itself is regulated by reversible association with various transcription factors/cofactors to form several multisubunit complexes [e.g., the 7SK small nuclear ribonucleoprotein particle (7SK snRNP), the super elongation complexes (SECs), and the bromodomain protein 4 (Brd4)-P-TEFb complex] that constitute a P-TEFb network controlling cellular and HIV transcription. These complexes have been thought to share no components other than the core P-TEFb subunits cyclin-dependent kinase 9 (CDK9) and cyclin T (CycT, T1, T2a, and T2b). Here we show that the AF4/FMR2 family member 1 (AFF1) is bound to CDK9-CycT and is present in all major P-TEFb complexes and that the tripartite CDK9-CycT-AFF1 complex is transferred as a single unit within the P-TEFb network. By increasing the affinity of the HIV-encoded transactivating (Tat) protein for CycT1, AFF1 facilitates Tat's extraction of P-TEFb from 7SK snRNP and the formation of Tat-SECs for HIV transcription. Our data identify AFF1 as a ubiquitous P-TEFb partner and demonstrate that full Tat transactivation requires the complete SEC.T ranscription by RNA polymerase II (Pol II) is a dynamic process consisting of several distinct but interconnected stages. Over the past three decades, much attention has been focused on the initiation and preinitiation stages of the transcription cycle, because they had been thought to be the principal points at which transcription is controlled (1, 2). Since 2007, however, accumulating evidence has revealed that promoter-proximal pausing of Pol II during early elongation is much more prevalent than previously thought, suggesting that intricate control of gene expression can occur frequently at this stage also (3, 4). Indeed, the importance of controlled pause and release of Pol II is illustrated by the observations that this process plays a prominent role in regulating cell growth, renewal, and differentiation (5, 6).Transcription of the integrated HIV-1 proviral genome is hypersensitive to elongation defects, thus making it an ideal model for elucidating the mechanism and factors that control elongation. It has long been known that in the absence of the HIVencoded transactivating protein (Tat), Pol II can initiate transcription from the viral promoter efficiently but pauses soon after the synthesis of a short RNA segment that folds into a stem-loop structure termed the "transactivation-response" (TAR) element. Tat overcomes Pol II pausing by recruiting the host positive transcription elongation factor b (P-TEFb) to the newly formed TAR RNA to stimulate the production of full-length HIV transcripts (7,8). Containing cyclin-dependent kinase 9 (CDK9) and cyclin T1 (CycT1), P-TEFb triggers the release of paused Pol II by phosphorylating and thereby antagonizing the inhibitory actions of two negative elongation factors, DSIF and NELF (5, 6). P-...

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Section: Aff1 Interacts With 7sk Snrnp Components La Ribonucleoproteinsupporting

confidence: 71%

AFF1 is a ubiquitous P-TEFb partner to enable Tat extraction of P-TEFb from 7SK snRNP and formation of SECs for HIV transactivation

Xue

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Tat can extract P-TEFb from the 7SK snRNP and this is important for efficient HIV replication. 15,16,41 The 7SK snRNP is not tightly associated with chromatin and is rapidly extracted from nuclei even at very low salt. 41 Expression of Tat in cells leads to disruption of the 7SK snRNP and the formation of a Tat•P-TEFb complex in the absence of any other viral proteins or the viral genome.…”

Section: Discussionmentioning

confidence: 99%

“…15,16,41 The 7SK snRNP is not tightly associated with chromatin and is rapidly extracted from nuclei even at very low salt. 41 Expression of Tat in cells leads to disruption of the 7SK snRNP and the formation of a Tat•P-TEFb complex in the absence of any other viral proteins or the viral genome. 15,16 However, components of the 7SK snRNP have been cross-linked to the HIV promoter and it has been suggested that the extraction of P-TEFb occurs at the promoter.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of HIV-1 Tat complexed with human P-TEFb and AFF4

Babayeva

Suwa

et al. 2014

Cell Cycle

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“…Thus, once Tat is made, HIV replication is sustained despite the return of cells to their resting state. To verify that JQ1 also affects this P-TEFb equilibrium, we performed glycerol gradient centrifugation to separate free P-TEFb and the 7SK snRNP in cell lysates under medium-salt (100 mM KCl) conditions, which extract these complexes but not BRD4 from its chromatin-bound state (22,28). Minute amounts of BRD4 were extracted from chromatin in untreated J⌬K cells with the medium-salt buffer ( Fig.…”

Section: Jq1mentioning

confidence: 99%

Bromodomain and Extra-terminal (BET) Bromodomain Inhibition Activate Transcription via Transient Release of Positive Transcription Elongation Factor b (P-TEFb) from 7SK Small Nuclear Ribonucleoprotein

Bartholomeeusen

Xiang

Fujinaga

et al. 2012

Journal of Biological Chemistry

179

162

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Background: P-TEFb regulates transcription elongation, cell growth, and proliferation. Results: BET bromodomain inhibition by JQ1 transiently releases free P-TEFb from the inactive 7SK snRNP, thus activating HEXIM1 and HIV transcription. Conclusion: JQ1 affects the P-TEFb equilibrium. Significance: P-TEFb release from and reassembly into 7SK snRNP by JQ1 inhibits tumor cell growth and reactivates latent HIV.

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Inhibition of HIV-1 replication by P-TEFb inhibitors DRB, seliciclib and flavopiridol correlates with release of free P-TEFb from the large, inactive form of the complex

Cited by 116 publications

References 54 publications

AFF1 is a ubiquitous P-TEFb partner to enable Tat extraction of P-TEFb from 7SK snRNP and formation of SECs for HIV transactivation

AFF1 is a ubiquitous P-TEFb partner to enable Tat extraction of P-TEFb from 7SK snRNP and formation of SECs for HIV transactivation

Crystal structure of HIV-1 Tat complexed with human P-TEFb and AFF4

Bromodomain and Extra-terminal (BET) Bromodomain Inhibition Activate Transcription via Transient Release of Positive Transcription Elongation Factor b (P-TEFb) from 7SK Small Nuclear Ribonucleoprotein

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