Dynamic remodelling of human 7SK snRNP controls the nuclear level of active P-TEFb

Herreweghe, Elodie Van; Egloff, Sylvain; Goiffon, Isabelle; Jády, Beáta E.; Froment, Carine; Monsarrat, Bernard; Kiss, Tamás

doi:10.1038/sj.emboj.7601783

Cited by 108 publications

(162 citation statements)

References 42 publications

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“…Overall, these findings suggest that in addition to the capping of 7SK by BCDIN3 and binding its 3Ј poly(U) tail by LARP7 (17,11), the extensive RNA-protein and protein-protein interactions within core 7SK snRNP guarantee its maintenance. Hence, core 7SK snRNP cannot be disintegrated when exposed to ActD, which explains the stability of 7SK under this cell stress-inducing condition and allows core 7SK snRNP to be a platform for the dynamic and reversible remodeling of 7SK snRNP as observed before (6,24,25).…”

Section: Discussionmentioning

confidence: 99%

“…S6 C-E). These EDA levels were not stimulated by hnRNP A1, an inhibitory splicing factor (23) present in a distinct 7SK snRNP complex devoid of P-TEFb (24,25), which is most likely also released from this 7SK snRNP upon depletion of LARP7 or BCDIN3. As expected, depletion of hnRNP A1 mRNA enhanced the inclusion of EDA (Fig.…”

Section: Disintegration Of 7sk Snrnp Promotes Alternative Splicing VImentioning

confidence: 99%

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7SK snRNP/P-TEFb couples transcription elongation with alternative splicing and is essential for vertebrate development

Barborič

Lenasi

Chen

et al. 2009

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

151

176

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Eukaryotic gene expression is commonly controlled at the level of RNA polymerase II (RNAPII) pausing subsequent to transcription initiation. Transcription elongation is stimulated by the positive transcription elongation factor b (P-TEFb) kinase, which is suppressed within the 7SK small nuclear ribonucleoprotein (7SK snRNP). However, the biogenesis and functional significance of 7SK snRNP remain poorly understood. Here, we report that LARP7, BCDIN3, and the noncoding 7SK small nuclear RNA (7SK) are vital for the formation and stability of a cell stress-resistant core 7SK snRNP. Our functional studies demonstrate that 7SK snRNP is not only critical for controlling transcription elongation, but also for regulating alternative splicing of pre-mRNAs. Using a transient expression splicing assay, we find that 7SK snRNP disintegration promotes inclusion of an alternative exon via the increased occupancy of P-TEFb, Ser2-phosphorylated (Ser2-P) RNAPII, and the splicing factor SF2/ASF at the minigene. Importantly, knockdown of larp7 or bcdin3 orthologues in zebrafish embryos destabilizes 7SK and causes severe developmental defects and aberrant splicing of analyzed transcripts. These findings reveal a key role for P-TEFb in coupling transcription elongation with alternative splicing, and suggest that maintaining core 7SK snRNP is essential for vertebrate development.C hallenging the once predominantly held view that RNA polymerase II (RNAPII) recruitment to promoters is the rate-limiting event in regulating eukaryotic transcription, several recent studies indicate that RNAPII pauses subsequently to transcription initiation at a large number of genes in Drosophila and in several cell lineages in humans (1). A paradigm for this type of control is the regulation of HIV-1 transcription, which is paused because of concerted actions of the negative transcription elongation factors (N-TEFs) (1, 2). The block is reversed by the positive transcription elongation factor b (P-TEFb), consisting of a heterodimer between the cyclin-dependent kinase 9 (Cdk9) and one of the four C-type cyclins (CycT1/T2a(b)/K) (2), which phosphorylates Ser2 within the multiple heptapeptide repeats YSPTSPS of the carboxy-terminal domain (CTD) of the Rpb1 subunit of RNAPII, as well as components of N-TEFs. Of note, P-TEFb is critical for expressing early embryonic genes in C. elegans (3), and experiments in yeast and Drosophila demonstrate that it is also vital for proper 3Ј end pre-mRNA processing (4, 5). Thus, regulating transcription elongation is a key checkpoint for modulating eukaryotic gene expression.P-TEFb exists in 2 mutually exclusive complexes that differ in their kinase activity (2). A transcriptionally inactive complex [referred to herein as 7SK small nuclear ribonucleoprotein (7SK snRNP)] contains P-TEFb, hexamethylene bisacetamide-induced protein (HEXIM) 1 (HEXIM1) and/or HEXIM2, the noncoding 7SK small nuclear RNA (7SK) and the La-related protein 7 (LARP7) (6-12). Therein, 7SK is a molecular scaffold, which binds HEXIM1, HEXIM2, and LARP7 d...

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Section: Discussionmentioning

confidence: 99%

Section: Disintegration Of 7sk Snrnp Promotes Alternative Splicing VImentioning

confidence: 99%

7SK snRNP/P-TEFb couples transcription elongation with alternative splicing and is essential for vertebrate development

Barborič

Lenasi

Chen

et al. 2009

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

151

176

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“…However, the outcome of the slow polymerase was an even greater decrease in miRNA synthesis. It is therefore anticipated that under certain physiological conditions in which PolII processivity is altered 40,41 or transcription re-initiation rate is regulated, 42 the effect on miRNA expression would be differential.…”

Section: Discussionmentioning

confidence: 99%

Disparity between microRNA levels and promoter strength is associated with initiation rate and Pol II pausing

et al. 2013

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MicroRNAs are transcribed by RNA polymerase II but the transcriptional features influencing their synthesis are poorly defined. Here we report that a TATA box in microRNA and proteincoding genes is associated with increased sensitivity to slow RNA polymerase II. Promoters driven by TATA box or NF-kB elicit high re-initiation rates, but paradoxically lower microRNA levels. MicroRNA synthesis becomes more productive by decreasing the initiation rate, but less productive when the re-initiation rate increases. This phenomenon is associated with a delay in miR-146a induction by NF-kB. Finally, we demonstrate that microRNAs are remarkably strong pause sites. Our findings suggest that lower efficiency of microRNA synthesis directed by TATA box or NF-kB is a consequence of frequent transcription initiations that lead to RNA polymerase II crowding at pause sites, thereby increasing the chance of collision and premature termination. These findings highlight the importance of the transcription initiation mechanism for microRNA synthesis, and have implications for TATA-box promoters in general.

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“…ribonucleoproteins) [12,13]. Ce mécanisme de régula-tion consiste donc à moduler la quantité de P-TEFb disponible pour activer la transcription.…”

Section: Synthèse Revuesunclassified

Perturbations de la transcription liées à une dérégulation de P-TEFb : cancer, Sida et hypertrophie cardiaque

2012

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Dynamic remodelling of human 7SK snRNP controls the nuclear level of active P-TEFb

Cited by 108 publications

References 42 publications

7SK snRNP/P-TEFb couples transcription elongation with alternative splicing and is essential for vertebrate development

7SK snRNP/P-TEFb couples transcription elongation with alternative splicing and is essential for vertebrate development

Disparity between microRNA levels and promoter strength is associated with initiation rate and Pol II pausing

Perturbations de la transcription liées à une dérégulation de P-TEFb : cancer, Sida et hypertrophie cardiaque

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