Alternative splicing: a pivotal step between eukaryotic transcription and translation

Kornblihtt, Alberto R.; Schor, Ignacio E.; Alló, Mariano; Dujardin, Geneviève; Petrillo, Ezequiel; Muñoz, Manuel J.

doi:10.1038/nrm3525

Cited by 718 publications

(717 citation statements)

References 142 publications

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“…8,10 For instance, the SWI/SNF subunit BRM, which also interacts with SAM68, was suggested to slow down RNAPII in the region encoding the variable exons of CD44, thereby favoring their recognition by the spliceosome and their inclusion in the mRNA. 50 To test whether SND1 also had its role in splicing by modulating the RNAPII elongation rate within the CD44 transcription unit, we analyzed the accumulation of nascent CD44 pre-mRNA following reversible inhibition of transcription by 5,6-Dichlorobenzimidazole 1-b-D-ribofuranoside (DRB) treatment.…”

Section: Identification Of Snd1 As a Novel Sam68-interacting Proteinmentioning

confidence: 99%

“…[7][8][9][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.…”

Section: Introductionmentioning

confidence: 99%

“…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 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.…”

Section: Introductionmentioning

confidence: 99%

“…On the contrary, a faster elongation rate is often associated with the skipping of weak exons. 7,8,10 The splicing machinery is an important target of misregulation in cancer. 14 In particular, changes in expression and/or activity of splicing factors and RNA-binding proteins (RBPs) correlate with cancer development, progression and response to therapy.…”

Section: Introductionmentioning

confidence: 99%

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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: Identification Of Snd1 As a Novel Sam68-interacting Proteinmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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“…Ainsi, nous avons identifié plasmide, induisaient des profils d'épis-sage différents [7]. Depuis, outre la nature du promoteur, il a été montré que des facteurs de transcription, des coactivateurs et des enhancers transcriptionnels, des facteurs de remodelage de la chromatine ou des facteurs qui affectent la structure de la chromatine, pouvaient également modifier l'épissage alternatif [8]. Pour expliquer ce méca-nisme de couplage entre la transcription par la Pol II et l'épissage alternatif, deux modèles, différents mais non exclusifs, ont été proposés : le modèle du recrutement de facteurs et le modèle cinétique.…”

Section: Augmentation De L'exclusion D'exons Lors Du Ralentissement Dunclassified

Régulation cinétique de l’épissage alternatif des pré-ARN messagers : attention au ralentissement

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Identification and functional comparison of novel alternatively spliced isoforms of human YAP

et al. 2023

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As a key effector of the Hippo pathway, yes‐associated protein (YAP) is a major regulator of cell proliferation and apoptosis. In this study, 23 hYAP isoforms were identified in HEK293 cells, with 14 isoforms being reported for the first time. These isoforms were classified into hYAP‐a and hYAP‐b isoforms based on the variation in exon 1. The two groups of isoforms showed distinctly different subcellular localizations. hYAP‐a isoforms could activate TEAD‐ or P73‐mediated transcription, affect the proliferation rate, and enhance the cellular chemosensitivity of HEK293 cells. Moreover, different activation abilities and pro‐cytotoxic effects were observed among hYAP‐a isoforms. However, hYAP‐b isoforms were not found to exert any significant biological effects. Our findings add to the knowledge of YAP gene structure and protein‐coding capacity and will help in the elucidation of the function and related molecular mechanisms of the Hippo‐YAP signaling pathway.

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Alternative splicing: a pivotal step between eukaryotic transcription and translation

Cited by 718 publications

References 142 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

Régulation cinétique de l’épissage alternatif des pré-ARN messagers : attention au ralentissement

Identification and functional comparison of novel alternatively spliced isoforms of human YAP

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