A La-Related Protein Modulates 7SK snRNP Integrity to Suppress P-TEFb-Dependent Transcriptional Elongation and Tumorigenesis

He, Nanhai; Jahchan, Nadine S.; Hong, Eunmee; Li, Qiang; Bayfield, Mark A.; Maraia, Richard J; Luo, Kunxin; Zhou, Qiang

doi:10.1016/j.molcel.2008.01.003

Cited by 221 publications

(316 citation statements)

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“…We immunopurified P-TEFb-or HEXIM1-associated factors from whole cell extracts (WCEs) of F1C2 or HH8 HeLa-based cell lines that stably expressed FLAG-tagged Cdk9 (Cdk9.F) or HEXIM1 (F.HEXIM1) proteins, respectively (6,9), and performed mass spectrometry of prominent bands. In agreement with recent work (11,12,17), we identified LARP7 and BCDIN3 as P-TEFb and HEXIM1 interacting partners (Table S1 and Table S2). Of note, the depletion of LARP7 destabilizes 7SK for 7SK snRNP disintegration and malignant transformation of a mammary epithelial cell line (11), and BCDIN3 is a 7SK ␥-methylphosphate capping enzyme (MePCE) essential for its stability (17).…”

Section: Larp7 and Bcdin3 Are Present In 7sk Snrnp And Interact Withsupporting

confidence: 91%

“…The dynamic partitioning of P-TEFb between the complexes constitutes a functional equilibrium that can be perturbed. For example, HIV-1 Tat increases the pool of active P-TEFb for optimal viral transcription by hijacking it from 7SK snRNP (15), and the disintegration of 7SK snRNP leads to cardiac hypertrophy or tumorigenesis (16,11).At present, little is known about the assembly and functional significance of maintaining 7SK snRNP in vivo. Here, we identify LARP7 and Bicoid-interacting 3, homolog (Drosophila) (BCDIN3) as vital components of 7SK snRNP, which in concert with 7SK govern the biogenesis and integrity of core 7SK snRNP.…”

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confidence: 99%

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confidence: 99%

“…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)(7)(8)(9)(10)(11)(12). Therein, 7SK is a molecular scaffold, which binds HEXIM1, HEXIM2, and LARP7 directly, enabling the sequestration and repression of P-TEFb.…”

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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

177

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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: Larp7 and Bcdin3 Are Present In 7sk Snrnp And Interact Withsupporting

confidence: 91%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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

177

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“…34,35 The structure explains sequence conservation and reveals motifs that may play roles in recognition of P-TEFb and the HEXIM proteins in addition to retroviral Tat. A preformed protein-binding pocket in the bulge is composed of a pseudo-triple platform and it is noteworthy that hydrogen bond formation is not required for complex formation.…”

Section: Summary and Implicationsmentioning

confidence: 99%

Preformed Protein-binding Motifs in 7SK snRNA: Structural and Thermodynamic Comparisons with Retroviral TAR

Durney

D'Souza

2010

Journal of Molecular Biology

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Compound heterozygous variants in the LARP7 gene as a cause of Alazami syndrome in a Caucasian female with significant failure to thrive, short stature, and developmental disability

Ling

Sorrentino

2015

American J of Med Genetics Pt A

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Alazami syndrome is an autosomal recessive disease characterized by primordial dwarfism, distinct dysmorphic features, and severe intellectual disability. Since it was first identified in a large consanguineous Arabic family in 2012, additional cases have not been published in the literature. We present a 2-year-old Northern European/Caucasian female with short stature, failure to thrive, and developmental delay. Whole exome sequencing (WES) identified two novel pathogenic variants in LARP7 (c.213_214dup and c.651_655del), indicating a diagnosis of Alazami syndrome. The case report describes a novel genotypic and phenotypic presentation of Alazami syndrome, contributing to the current knowledge of the condition as well as the expansion of differential diagnoses for growth restriction and intellectual disability.

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A La-Related Protein Modulates 7SK snRNP Integrity to Suppress P-TEFb-Dependent Transcriptional Elongation and Tumorigenesis

Cited by 221 publications

References 34 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

Preformed Protein-binding Motifs in 7SK snRNA: Structural and Thermodynamic Comparisons with Retroviral TAR

Compound heterozygous variants in the LARP7 gene as a cause of Alazami syndrome in a Caucasian female with significant failure to thrive, short stature, and developmental disability

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