The splicing factor SC35 has an active role in transcriptional elongation

Lin, Shengrong; Coutinho-Mansfield, Gabriela; Wang, Dong; Pandit, Shatakshi; Fu, Xiang‐Dong

doi:10.1038/nsmb.1461

Cited by 331 publications

(355 citation statements)

References 53 publications

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“…4 D and E), suggesting the bidirectional coupling between transcription elongation and cotranscriptional splicing. These results are consistent with a recent report, which demonstrated that another SR protein SC35 was required for efficient transcription elongation, P-TEFb recruitment, and CTD Ser2 phosphorylation in a gene-specific manner (27). We conclude that disintegration of 7SK snRNP leads to the P-TEFb-mediated phosphorylation of the CTD of RNAPII at Ser2, thereby facilitating the recruitment of the stimulatory splicing factor SF2/ ASF for promoting EDA inclusion levels.…”

Section: P-tefb Promotes Alternative Splicing Via Ser2-p Rnapii and Ssupporting

confidence: 82%

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: P-tefb Promotes Alternative Splicing Via Ser2-p Rnapii and Ssupporting

confidence: 82%

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

View full text Add to dashboard Cite

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“…It is known that addition of a 5' splice site can activate transcription elongation, and that splicing factors can stimulate elongation by RNAPII. 65 Lastly, a competition may exist between the formation of the sense and anti-sense transcription complexes and the efficiency of PIC assembly on either side of transcription factor binding sites may impact transcription directionality. Activation of members of the KIR and Ly49 family of receptor genes in human and mice, respectively, is thought to be controlled by the relative strength of a competing promoter that directs divergent transcription upstream of the promoters.…”

Section: One Way or Another?mentioning

confidence: 99%

Divergent transcription: A new feature of active promoters

Seila¹,

Core²,

Lis³

et al. 2009

Cell Cycle

168

164

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“…9,10 Such regulation may also act bidirectionally, as splicing factors bound to complexes on nascent pre-mRNA can also modulate transcription. 11,12 For instance, the splicing factor SRSF2 (SC35) was shown to influence the post-translational modification of RNAPII and, as a consequence, its elongation rate. 12 A second model, known as 'kinetic model', proposes that changes in RNAPII elongation rate modulate exon inclusion by altering the availability of suboptimal splice sites.…”

Section: Introductionmentioning

confidence: 99%

“…11,12 For instance, the splicing factor SRSF2 (SC35) was shown to influence the post-translational modification of RNAPII and, as a consequence, its elongation rate. 12 A second model, known as 'kinetic model', proposes that changes in RNAPII elongation rate modulate exon inclusion by altering the availability of suboptimal splice sites. 13 In particular, a slow elongation rate allows the splicing factors to recognize weak splice site on the nascent transcripts, thus favoring the inclusion of variable exons in the mature mRNA.…”

Section: Introductionmentioning

confidence: 99%

The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells

et al. 2013

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Splicing abnormalities have profound impact in human cancer. Several splicing factors, including SAM68, have pro-oncogenic functions, and their increased expression often correlates with human cancer development and progression. Herein, we have identified using mass spectrometry proteins that interact with endogenous SAM68 in prostate cancer (PCa) cells. Among other interesting proteins, we have characterized the interaction of SAM68 with SND1, a transcriptional co-activator that binds spliceosome components, thus coupling transcription and splicing. We found that both SAM68 and SND1 are upregulated in PCa cells with respect to benign prostate cells. Upregulation of SND1 exerts a synergic effect with SAM68 on exon v5 inclusion in the CD44 mRNA. The effect of SND1 on CD44 splicing required SAM68, as it was compromised after knockdown of this protein or mutation of the SAM68-binding sites in the CD44 pre-mRNA. More generally, we found that SND1 promotes the inclusion of CD44 variable exons by recruiting SAM68 and spliceosomal components on CD44 pre-mRNA. Inclusion of the variable exons in CD44 correlates with increased proliferation, motility and invasiveness of cancer cells. Strikingly, we found that knockdown of SND1, or SAM68, reduced proliferation and migration of PCa cells. Thus, our findings strongly suggest that SND1 is a novel regulator of alternative splicing that promotes PCa cell growth and survival.Oncogene advance online publication, 2 September 2013; doi:10.1038/onc.2013.360Keywords: alternative splicing; SND1; SAM68; CD44; prostate cancer INTRODUCTION Nuclear processing of pre-mRNAs requires tightly regulated steps that ultimately yield a mature and functional mRNA. Splicing is the step that insures the removal of long non-coding sequences (introns) from the pre-mRNA and the joining of the exons. This phenomenon is driven by a large macromolecular complex, the spliceosome, composed of five small nuclear ribonucleoproteins (snRNPs) and over 200 auxiliary proteins. 1 In higher eukaryotes, a large number of exons can be alternatively spliced to yield different transcripts from a single gene, thereby increasing the coding potential of the genome. 2,3 Indeed, the large majority of multi-exon human genes undergo alternative splicing (AS) to produce at least two mRNA variants. 4,5 As regulation of AS profoundly influences physiological and pathological processes, 3,6 the full comprehension of the molecular mechanisms regulating this step of pre-mRNA processing is of fundamental importance.Splicing is physically and functionally coupled to transcription. 7-10 Two models have been proposed for how transcription might affect changes in AS patterns. The 'recruitment model' suggests that the transcription apparatus physically interacts with splicing regulators, thereby affecting splicing decisions. The C-terminal domain (CTD) of the largest subunit of the RNA polymerase II (RNAPII) has a central role in this coupling process by favoring the recruitment of RNA processing factors on the nascent transcripts. 9,10 ...

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The splicing factor SC35 has an active role in transcriptional elongation

Cited by 331 publications

References 53 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

Divergent transcription: A new feature of active promoters

The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells

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