7SK small nuclear RNA, a multifunctional transcriptional regulatory RNA with gene-specific features

Egloff, Sylvain; Studniarek, Cécilia; Kiss, Tamás

doi:10.1080/21541264.2017.1344346

Cited by 40 publications

(26 citation statements)

References 31 publications

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“…Purified recombinant WT and Δ38 NS proteins were equilibrated with terminally radiolabeled uncapped and nonpolyadenylated stem I 7SK small nuclear RNA (snRNA). The 7SK snRNA is a highly structured RNA that functions to regulate transcription in metazoans (54). Stem I of the 7SK snRNA encompasses the first 108 nucleotides, which are organized as a GC-rich stem-loop (55).…”

Section: Figmentioning

confidence: 99%

Reovirus Nonstructural Protein σNS Acts as an RNA Stability Factor Promoting Viral Genome Replication

Zamora

Knowlton

et al. 2018

J Virol

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Viral nonstructural proteins, which are not packaged into virions, are essential for the replication of most viruses. Reovirus, a nonenveloped, double-stranded RNA (dsRNA) virus, encodes three nonstructural proteins that are required for viral replication and dissemination in the host. The reovirus nonstructural protein σNS is a single-stranded RNA (ssRNA)-binding protein that must be expressed in infected cells for production of viral progeny. However, the activities of σNS during individual steps of the reovirus replication cycle are poorly understood. We explored the function of σNS by disrupting its expression during infection using cells expressing a small interfering RNA (siRNA) targeting the σNS-encoding S3 gene and found that σNS is required for viral genome replication. Using complementary biochemical assays, we determined that σNS forms complexes with viral and nonviral RNAs. We also discovered, using and cell-based RNA degradation experiments, that σNS increases the RNA half-life. Cryo-electron microscopy revealed that σNS and ssRNAs organize into long, filamentous structures. Collectively, our findings indicate that σNS functions as an RNA-binding protein that increases the viral RNA half-life. These results suggest that σNS forms RNA-protein complexes in preparation for genome replication. Following infection, viruses synthesize nonstructural proteins that mediate viral replication and promote dissemination. Viruses from the family encode nonstructural proteins that are required for the formation of progeny viruses. Although nonstructural proteins of different viruses in the family diverge in primary sequence, they are functionally homologous and appear to facilitate conserved mechanisms of dsRNA virus replication. Using and cell culture approaches, we found that the mammalian reovirus nonstructural protein σNS binds and stabilizes viral RNA and is required for genome synthesis. This work contributes new knowledge about basic mechanisms of dsRNA virus replication and provides a foundation for future studies to determine how viruses in the family assort and replicate their genomes.

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Section: Figmentioning

confidence: 99%

Reovirus Nonstructural Protein σNS Acts as an RNA Stability Factor Promoting Viral Genome Replication

Zamora

Knowlton

et al. 2018

J Virol

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“…These include ncRNAs involved in splicing of pre-mRNAs (snRNAs) 24,25 , cleavage and modification of pre-ribosomal RNAs (snoRNAs, Rnase MRP) [26][27][28] , 3'-end cleavage and processing of the non-polyadenylated histone pre-mRNAs (U7 snRNA) [29][30][31][32] , and transcriptional regulation (e.g. Xist [33][34][35] and 7SK [36][37][38] ). Interestingly, many of these functionally important ncRNAs localize within specific spatial compartments in the nucleus 6,39,40 .…”

Section: Introductionmentioning

confidence: 99%

RNA promotes the formation of spatial compartments in the nucleus

Quinodoz

Bhat

Ollikainen

et al. 2020

Preprint

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The nucleus is a highly organized arrangement of RNA, DNA, and protein molecules that are compartmentalized within three-dimensional (3D) structures involved in shared functional and regulatory processes. Although RNA has long been proposed to play a global role in organizing nuclear structure, exploring the role of RNA in shaping nuclear structure has remained a challenge because no existing methods can simultaneously measure RNA-RNA, RNA-DNA, and DNA-DNA contacts within 3D structures. To address this, we developed RNA & DNA SPRITE (RD-SPRITE) to comprehensively map the location of all RNAs relative to DNA and other RNAs. Using this approach, we identify many RNAs that are localized near their transcriptional loci (RNA-DNA) together with other diffusible ncRNAs (RNA-RNA) within higher-order DNA structures (DNA-DNA). These RNA-chromatin compartments span three major classes of nuclear functions: RNA processing (including ribosome biogenesis, mRNA splicing, snRNA biogenesis, and histone mRNA processing), heterochromatin assembly, and gene regulation. More generally, we identify hundreds of ncRNAs that form stable nuclear compartments in spatial proximity to their transcriptional loci. We find that dozens of nuclear compartments require RNA to guide protein regulators into these 3D structures, and focusing on several ncRNAs, we show that these ncRNAs specifically regulate heterochromatin assembly and the expression of genes contained within these compartments. Together, our results demonstrate a unique mechanism by which RNA acts to shape nuclear structure by forming high concentration territories immediately upon transcription, binding to diffusible regulators, and guiding them into spatial compartments to regulate a wide range of essential nuclear functions.

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“…Furthermore, P-TEFb is an essential host cofactor for HIV replication (41,42), where it is hijacked from the 7SK RNP by the transactivator of transcription protein and recruited to stalled HIV genomic transcripts (43)(44)(45)(46)(47). Beyond regulation of P-TEFb, 7SK also regulates the RNAPII transcription of small nuclear RNAs (48) as well as enhancer RNAs (49) and interacts with hnRNP R to regulate its function in axon maintenance (50).…”

mentioning

confidence: 99%

Structural basis for recognition of human 7SK long noncoding RNA by the La-related protein Larp7

Eichhorn

Yang

Repeta

et al. 2018

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

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The La and the La-related protein (LARP) superfamily is a diverse class of RNA binding proteins involved in RNA processing, folding, and function. Larp7 binds to the abundant long noncoding 7SK RNA and is required for 7SK ribonucleoprotein (RNP) assembly and function. The 7SK RNP sequesters a pool of the positive transcription elongation factor b (P-TEFb) in an inactive state; on release, P-TEFb phosphorylates RNA Polymerase II to stimulate transcription elongation. Despite its essential role in transcription, limited structural information is available for the 7SK RNP, particularly for protein-RNA interactions. Larp7 contains an N-terminal La module that binds UUU-3'OH and a C-terminal atypical RNA recognition motif (xRRM) required for specific binding to 7SK and P-TEFb assembly. Deletion of the xRRM is linked to gastric cancer in humans. We report the 2.2-Å X-ray crystal structure of the human La-related protein group 7 (hLarp7) xRRM bound to the 7SK stem-loop 4, revealing a unique binding interface. Contributions of observed interactions to binding affinity were investigated by mutagenesis and isothermal titration calorimetry. NMR C spin relaxation data and comparison of free xRRM, RNA, and xRRM-RNA structures show that the xRRM is preordered to bind a flexible loop 4. Combining structures of the hLarp7 La module and the xRRM-7SK complex presented here, we propose a structural model for Larp7 binding to the 7SK 3' end and mechanism for 7SK RNP assembly. This work provides insight into how this domain contributes to 7SK recognition and assembly of the core 7SK RNP.

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7SK small nuclear RNA, a multifunctional transcriptional regulatory RNA with gene-specific features

Cited by 40 publications

References 31 publications

Reovirus Nonstructural Protein σNS Acts as an RNA Stability Factor Promoting Viral Genome Replication

Reovirus Nonstructural Protein σNS Acts as an RNA Stability Factor Promoting Viral Genome Replication

RNA promotes the formation of spatial compartments in the nucleus

Structural basis for recognition of human 7SK long noncoding RNA by the La-related protein Larp7

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