Post-transcriptional spliceosomes are retained in nuclear speckles until splicing completion

Girard, Cyrille; Will, Cindy L.; Peng, Jianhe; Makarov, Evgeny M.; Kastner, Berthold; Lemm, Ira; Urlaub, Henning; Hartmuth, Klaus; Lührmann, Reinhard

doi:10.1038/ncomms1998

Cited by 242 publications

(294 citation statements)

References 56 publications

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“…These observations are in very good agreement with our view that in cells treated with SF3b inhibitors, pre-mRNAs are retained through interactions with spliceosomal components localized in the speckles. The establishment of interactions between RNAs and spliceosomal components at speckles is further supported by recent evidence suggesting the involvement of nuclear speckles in posttranscriptional splicing (Girard et al, 2012;Mor et al, 2016).…”

Section: Discussionsupporting

confidence: 53%

Pharmacological inhibition of the spliceosome subunit SF3b triggers exon junction complex-independent nonsense-mediated decay

Carvalho

Martins

Rino

et al. 2017

Journal of Cell Science

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Spliceostatin A, meayamycin, and pladienolide B are small molecules that target the SF3b subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP). These compounds are attracting much attention as tools to manipulate splicing and for use as potential anticancer drugs. We investigated the effects of these inhibitors on mRNA transport and stability in human cells. Upon splicing inhibition, unspliced pre-mRNAs accumulated in the nucleus, particularly within enlarged nuclear speckles. However, a small fraction of the premRNA molecules were exported to the cytoplasm. We identified the export adaptor ALYREF as being associated with intron-containing transcripts and show its requirement for the nucleo-cytoplasmic transport of unspliced pre-mRNA. In contrast, the exon junction complex (EJC) core protein eIF4AIII failed to form a stable complex with intron-containing transcripts. Despite the absence of EJC, unspliced transcripts in the cytoplasm were degraded by nonsensemediated decay (NMD), suggesting that unspliced transcripts are degraded by an EJC-independent NMD pathway. Collectively, our results indicate that although blocking the function of SF3b elicits a massive accumulation of unspliced pre-mRNAs in the nucleus, intron-containing transcripts can still bind the ALYREF export factor and be transported to the cytoplasm, where they trigger an alternative NMD pathway.

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Section: Discussionsupporting

confidence: 53%

Pharmacological inhibition of the spliceosome subunit SF3b triggers exon junction complex-independent nonsense-mediated decay

Carvalho

Martins

Rino

et al. 2017

Journal of Cell Science

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“…Introns in sporadic constitutive genes are detectable in the nucleoplasmic fraction, and imaging data indicate that some introns may be excised away from their chromatin template (Supplemental Fig. S1; Vargas et al 2011;Girard et al 2012). However, measurements of steady-state RNA levels from most constitutive genes found intronic RNA sequence primarily in the chromatin fraction (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

Splicing kinetics and transcript release from the chromatin compartment limit the rate of Lipid A-induced gene expression

Pandya-Jones

Bhatt

Lin

et al. 2013

RNA

104

102

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The expression of eukaryotic mRNAs is achieved though an intricate series of molecular processes that provide many steps for regulating the production of a final gene product. However, the relationships between individual steps in mRNA biosynthesis and the rates at which they occur are poorly understood. By applying RNA-seq to chromatin-associated and soluble nucleoplasmic fractions of RNA from Lipid A-stimulated macrophages, we examined the timing of exon ligation and transcript release from chromatin relative to the induction of transcription. We find that for a subset of genes in the Lipid A response, the ligation of certain exon pairs is delayed relative to the synthesis of the complete transcript. In contrast, 3′ end cleavage and polyadenylation occur rapidly once transcription extends through the cleavage site. Our data indicate that these transcripts with delayed splicing are not released from the chromatin fraction until all the introns have been excised. These unusual kinetics result in a chromatin-associated pool of completely transcribed and 3 ′ -processed transcripts that are not yet fully spliced. We also find that long introns containing repressed exons that will be excluded from the final mRNA are excised particularly slowly relative to other introns in a transcript. These results indicate that the kinetics of splicing and transcript release contribute to the timing of expression for multiple genes of the inflammatory response.

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“…Until recently, speckles were thought to be storage sites of splicing factors (Spector and Lamond, 2011). However, a recent demonstration of the presence of a protein that is part of catalytically active spliceosomes in speckles and the presence of spliceosomes near or within the speckles indicate that posttranscriptional splicing may occur in speckles (Girard et al, 2012). Little is known about the biogenesis of nonmembranous bodies containing RNA and proteins.…”

Section: Subcellular Localization and Dynamics Of Trans-acting Factorsmentioning

confidence: 99%

Complexity of the Alternative Splicing Landscape in Plants

et al. 2013

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Alternative splicing (AS) of precursor mRNAs (pre-mRNAs) from multiexon genes allows organisms to increase their coding potential and regulate gene expression through multiple mechanisms. Recent transcriptome-wide analysis of AS using RNA sequencing has revealed that AS is highly pervasive in plants. Pre-mRNAs from over 60% of intron-containing genes undergo AS to produce a vast repertoire of mRNA isoforms. The functions of most splice variants are unknown. However, emerging evidence indicates that splice variants increase the functional diversity of proteins. Furthermore, AS is coupled to transcript stability and translation through nonsense-mediated decay and microRNA-mediated gene regulation. Widespread changes in AS in response to developmental cues and stresses suggest a role for regulated splicing in plant development and stress responses. Here, we review recent progress in uncovering the extent and complexity of the AS landscape in plants, its regulation, and the roles of AS in gene regulation. The prevalence of AS in plants has raised many new questions that require additional studies. New tools based on recent technological advances are allowing genome-wide analysis of RNA elements in transcripts and of chromatin modifications that regulate AS. Application of these tools in plants will provide significant new insights into AS regulation and crosstalk between AS and other layers of gene regulation.

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Post-transcriptional spliceosomes are retained in nuclear speckles until splicing completion

Cited by 242 publications

References 56 publications

Pharmacological inhibition of the spliceosome subunit SF3b triggers exon junction complex-independent nonsense-mediated decay

Pharmacological inhibition of the spliceosome subunit SF3b triggers exon junction complex-independent nonsense-mediated decay

Splicing kinetics and transcript release from the chromatin compartment limit the rate of Lipid A-induced gene expression

Complexity of the Alternative Splicing Landscape in Plants

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