Stimulatory effect of splicing factors on transcriptional elongation

Fong, Yick W.; Zhou, Qiang

doi:10.1038/414929a

Cited by 308 publications

(274 citation statements)

References 29 publications

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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%

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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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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“…An attractive extension of this interpretation is that RNA binding proteins associate at promoters to modulate the elongation rate and downstream splicing decisions. Thus, cotranscriptional alternative splicing decisions may be the sum of both promoter and local interaction effects (Enriquez-Harris et al 1991;Cramer et al 1999;Fong and Zhou 2001;de la Mata et al 2003).…”

Section: Rna Binding Proteins Interact With Promoter Regionsmentioning

confidence: 99%

Genomic localization of RNA binding proteins reveals links between pre-mRNA processing and transcription

Swinburne

Meyer²,

Liu³

et al. 2006

Genome Res.

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Pre-mRNA processing often occurs in coordination with transcription thereby coupling these two key regulatory events. As such, many proteins involved in mRNA processing associate with the transcriptional machinery and are in proximity to DNA. This proximity allows for the mapping of the genomic associations of RNA binding proteins by chromatin immunoprecipitation (ChIP) as a way of determining their sites of action on the encoded mRNA. Here, we used ChIP combined with high-density microarrays to localize on the human genome three functionally distinct RNA binding proteins: the splicing factor polypyrimidine tract binding protein (PTBP1/hnRNP I), the mRNA export factor THO complex subunit 4 (ALY/THOC4), and the 3Ј end cleavage stimulation factor 64 kDa (CSTF2). We observed interactions at promoters, internal exons, and 3Ј ends of active genes. PTBP1 had biases toward promoters and often coincided with RNA polymerase II (RNA Pol II). The 3Ј processing factor, CSTF2, had biases toward 3Ј ends but was also observed at promoters. The mRNA processing and export factor, ALY, mapped to some exons but predominantly localized to introns and did not coincide with RNA Pol II. Because the RNA binding proteins did not consistently coincide with RNA Pol II, the data support a processing mechanism driven by reorganization of transcription complexes as opposed to a scanning mechanism. In sum, we present the mapping in mammalian cells of RNA binding proteins across a portion of the genome that provides insight into the transcriptional assembly of RNA-protein complexes.[Supplemental material is available online at www.genome.org and http://silver.med.harvard.edu/brodsky/.] RNA binding proteins regulate many stages of RNA metabolism to help determine gene expression programs (for reviews, see Keene and Tenenbaum 2002;Hieronymus and Silver 2004). To prepare mRNA for export to and translation in the cytoplasm, many events including splicing, cleavage of the 3Ј end, and editing occur cotranscriptionally (Kornblihtt et al. 2004;Aguilera 2005a). After transcription, the mRNA-protein complex may reorganize as it is exported to the cytoplasm and prepared for translation (Fairman et al. 2004). Thus, significant efforts have been made to determine how RNA binding proteins interact at genes and/or mRNAs at various stages of mRNA metabolism (Tenenbaum et al. 2000;Brown et al. 2001;Hieronymus and Silver 2003;Ule et al. 2003;Yu et al. 2004). These early genomic efforts suggested that, similar to DNA binding proteins, functional groupings of genes are being bound by RNA binding proteins perhaps as post-transcriptional operons (Keene and Tenenbaum 2002). However, it is not known at which stage of RNA processing these operons are established.Much of pre-mRNA processing is coupled to transcription both physically and functionally, potentially through interactions with the C-terminal domain (CTD) of RNA polymerase II (RNA Pol II) (Mortillaro et al. 1996;Yuryev et al. 1996;Kim et al. 1997). The CTD is phosphorylated as transcription begins. Following...

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“…1 The recruited complexes are subsequently transferred onto nascent transcripts for the addition of a 5' cap structure, the removal of introns by the spliceosome, and the addition of a 3' poly(A) tail. [2][3][4] Studies during the past decade have shed light on evolutionarily conserved quality control systems that monitor the accuracy of these maturation events before an mRNA is exported through the nuclear pore complex, [5][6][7][8] thereby improving the fidelity of gene expression. Interestingly, evidence now converge toward the nature of the poly(A) tail as a critical mean of discriminating between normal and aberrant mRNAs.…”

Section: Introduction: Current View Of Mrna 3' End Processing and Nucmentioning

confidence: 99%

Crossing the borders: Poly(A)-binding proteins working on both sides of the fence

Lemay

Lemieux²,

St-André³

et al. 2010

RNA Biology

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T he addition of a 3' poly(A) tail is a pre-requisite for the maturation of the majority of eukaryotic transcripts. In most eukaryotic species, RNA poly(A) tails are bound by two important poly(A)-binding proteins (PABPs): PABPC1 and PABPN1 that localize to the cytoplasm and the nucleus, respectively. Such steady state localization for PABPN1 and PABPC1 led to a model whereby PABPN1-bound nuclear mRNAs are remodeled during or after nuclear export so that PABPN1 is replaced by PABPC1 to allow robust cap-dependent translation in the cytoplasm. Here we discuss evidence that challenge the view in which PABPN1 and PABPC1 function solely in the nucleus and cytoplasm, respectively. We discuss accumulating evidence that support nuclear roles for PABPC1 in mRNA biogenesis as well as cytoplasmic roles for PABPN1 in translational control. Because 3' poly(A) tails can also act as a degradation mark via the exosome complex of 3'-5' exonucleases, we also discuss recent results that involve the nuclear PABP in posttranscriptional gene regulation.

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Stimulatory effect of splicing factors on transcriptional elongation

Cited by 308 publications

References 29 publications

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

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

Genomic localization of RNA binding proteins reveals links between pre-mRNA processing and transcription

Crossing the borders: Poly(A)-binding proteins working on both sides of the fence

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