P-TEFb: Finding its ways to release promoter-proximally paused RNA polymerase II

Li, You; Liu, Min; Chen, Linfeng; Chen, Ruichuan

doi:10.1080/21541264.2017.1281864

Cited by 38 publications

(33 citation statements)

References 31 publications

(80 reference statements)

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“…Absence of ARS2 here might, directly or indirectly, affect the activity of factors involved in RNAPII stalling or stall site-release. It is for example, interesting to note that ARS2 associates with 7SK RNA ( 24 ), which sequesters the early transcription elongation factor P-TEFB in its inactive form ( 43 ). P-TEFB has also been reported to associate with the CBC ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

ARS2 is a general suppressor of pervasive transcription

Iasillo

Schmid

Yahia

et al. 2017

Nucleic Acids Research

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Termination of transcription is important for establishing gene punctuation marks. It is also critical for suppressing many of the pervasive transcription events occurring throughout eukaryotic genomes and coupling their RNA products to efficient decay. In human cells, the ARS2 protein has been implicated in such function as its depletion causes transcriptional read-through of selected gene terminators and because it physically interacts with the ribonucleolytic nuclear RNA exosome. Here, we study the role of ARS2 on transcription and RNA metabolism genome wide. We show that ARS2 depletion negatively impacts levels of promoter-proximal RNA polymerase II at protein-coding (pc) genes. Moreover, our results reveal a general role of ARS2 in transcription termination-coupled RNA turnover at short transcription units like snRNA-, replication-dependent histone-, promoter upstream transcript- and enhancer RNA-loci. Depletion of the ARS2 interaction partner ZC3H18 mimics the ARS2 depletion, although to a milder extent, whereas depletion of the exosome core subunit RRP40 only impacts RNA abundance post-transcriptionally. Interestingly, ARS2 is also involved in transcription termination events within first introns of pc genes. Our work therefore establishes ARS2 as a general suppressor of pervasive transcription with the potential to regulate pc gene expression.

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Section: Discussionmentioning

confidence: 99%

ARS2 is a general suppressor of pervasive transcription

Iasillo

Schmid

Yahia

et al. 2017

Nucleic Acids Research

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“…Briefly, Tat is a small viral protein comprising 101 amino acids, in most HIV strains, encoded by two exons (Figure 1a) [30]. The first exon encodes 72 amino acids and is divided into 5 regions: a proline-rich acidic N-terminus (amino acids 1-21), a cysteine-rich region (amino acids 22-37), a hydrophobic core region (amino acids [38][39][40][41][42][43][44][45][46][47][48], an arginine-rich basic region (amino acids [49][50][51][52][53][54][55][56][57], and a glutamine-rich region (amino acids 58-72). Exon 2 encodes a C-terminal domain.…”

Section: Tat Transactivation Of Hiv Transcriptionmentioning

confidence: 99%

“…A key point is that the HIV promoter is capable of a low basal level of transcription [37], that may stochastically produce a full length viral mRNA [22,38], which can be spliced into tat-encoding mRNA. The availability of Tat in an HIV-infected cell initiates a powerful feedback system that greatly increases HIV transcription (reviewed in [29,39]). Briefly, the activation domain of Tat can bind to the positive transcription elongation factor b (P-TEFb), a cellular complex composed of cyclin T1 (CycT1) and CDK9.…”

Section: A Tat-based Block-and-lock Functional Cure Strategymentioning

confidence: 99%

Tat-Based Therapies as an Adjuvant for an HIV-1 Functional Cure

Jin

Lin

et al. 2020

Viruses

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The human immunodeficiency virus type 1 (HIV) establishes a chronic infection that can be well controlled, but not cured, by combined antiretroviral therapy (cART). Interventions have been explored to accomplish a functional cure, meaning that a patient remains infected but HIV is undetectable in the blood, with the aim of allowing patients to live without cART. Tat, the viral transactivator of transcription protein, plays a critical role in controlling HIV transcription, latency, and viral rebound following the interruption of cART treatment. Therefore, a logical approach for controlling HIV would be to block Tat. Tackling Tat with inhibitors has been a difficult task, but some recent discoveries hold promise. Two anti-HIV proteins, Nullbasic (a mutant of Tat) and HT1 (a fusion of HEXIM1 and Tat functional domains) inhibit viral transcription by interfering with the interaction of Tat and cellular factors. Two small molecules, didehydro-cortistatin A (dCA) and triptolide, inhibit Tat by different mechanisms: dCA through direct binding and triptolide through enhanced proteasomal degradation. Finally, two Tat-based vaccines under development elicit Tat-neutralizing antibodies. These vaccines have increased the levels of CD4+ cells and reduced viral loads in HIV-infected people, suggesting that the new vaccines are therapeutic. This review summarizes recent developments of anti-Tat agents and how they could contribute to a functional cure for HIV.

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“…Hexim1 has been isolated from cell extracts bound to the inactive positive transcription factor (P-TEFb) complex and 7SK RNA [20]. P-TEFb is required to release RNA polymerase II pausing to achieve productive transcription of most Pol II genes [29][30][31]. Hence, Hexim1 and 7SK RNA act as transcription repressors.…”

Section: Sk Rna Binding Turns Hexim1 Into a P-tefb Inhibitormentioning

confidence: 99%

Hexim1, an RNA-controlled protein hub

Michels

Bensaude

2018

Transcription

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Hexim1 acts as a tumor suppressor and is involved in the regulation of innate immunity. It was initially described as a non-coding RNA-dependent regulator of transcription. Here, we detail how 7SK RNA binds to Hexim1 and turns it into an inhibitor of the positive transcription elongation factor (P-TEFb). In addition to its action on P-TEFb, it plays a role in a variety of different mechanisms: it controls the stability of transcription factor components and assists binding of transcription factors to their targets.

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P-TEFb: Finding its ways to release promoter-proximally paused RNA polymerase II

Cited by 38 publications

References 31 publications

ARS2 is a general suppressor of pervasive transcription

ARS2 is a general suppressor of pervasive transcription

Tat-Based Therapies as an Adjuvant for an HIV-1 Functional Cure

Hexim1, an RNA-controlled protein hub

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