SRSF1 regulates the assembly of pre-mRNA processing factors in nuclear speckles

Tripathi, Vidisha; Song, David; Zong, Xinying; Shevtsov, Sergey P.; Hearn, Stephen; Fu, Xiang Dong; Dundr, Miroslav; Prasanth, Kannanganattu V.

doi:10.1091/mbc.e12-03-0206

Cited by 108 publications

(85 citation statements)

References 72 publications

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“…Within nucleoplasm, mRNA splicing factors and RNA poymerase II are colocalized in specialized foci, called nuclear speckles or interchromatin granules clusters [290] and surrounded by assembly sites for exon junction core complexes [291]. Nuclear speckles are associated with NM proteins [25,292], and regulate/modulate both transcriptional and post-transcriptional events [293]. Nuclear speckles are also involved in the processing and export of transcripts from genes encoding mitochondrialor ER-targeted proteins and characterized by intron-free 5 UTR [294].…”

Section: Dna Replication Transcription Repair and Epigenetic Defectmentioning

confidence: 99%

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Cau

Navarro

Harhouri

et al. 2014

Seminars in Cell & Developmental Biology

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Lamin A-related progeroid syndromes are genetically determined, extremely rare and severe. In the past ten years, our knowledge and perspectives for these diseases has widely progressed, through the progressive dissection of their pathophysiological mechanisms leading to precocious and accelerated aging, from the genes mutations discovery until therapeutic trials in affected children. A-type lamins are major actors in several structural and functional activities at the nuclear periphery, as they are major components of the nuclear lamina. However, while this is usually poorly considered, they also play a key role within the rest of the nucleoplasm, whose defects are related to cell senescence. Although nuclear shape and nuclear envelope deformities are obvious and visible events, nuclear matrix disorganization and abnormal composition certainly represent the most important causes of cell defects with dramatic pathological consequences. Therefore, lamin-associated diseases should be better referred as laminopathies instead of envelopathies, this later being too restrictive, considering neither the key structural and functional roles of soluble lamins in the entire nucleoplasm, nor the nuclear matrix contribution to the pathophysiology of lamin-associated disorders and in particular in defective lamin A processing-associated aging diseases. Based on both our understanding of pathophysiological mechanisms and the biological and clinical consequences of progeria and related diseases, therapeutic trials have been conducted in patients and were terminated less than 10 years after the gene discovery, a quite fast issue for a genetic disease. Pharmacological drugs have been repurposed and used to decrease the toxicity of the accumulated, unprocessed and truncated prelaminA in progeria. To date, none of them may be considered as a cure for progeria and these clinical strategies were essentially designed toward reducing a subset of the most dramatic and morbid features associated to progeria. New therapeutic strategies under study, in particular targeting the protein expression pathway at the mRNA level, have shown a remarkable efficacy both in vitro in cells and in vivo in mice models. Strategies intending to clear the toxic accumulated proteins from the nucleus are also under evaluation. However, although exceedingly rare, improving our knowledge of genetic progeroid syndromes and searching for innovative and efficient therapies in these syndromes is of paramount importance as, even before they can be used to save lives, they may significantly (i) expand the affected childrens' lifespan and preserve their quality of life; (ii) improve our understanding of aging-related disorders and other more common diseases; and (iii) expand our fundamental knowledge of physiological aging and its links with major physiological processes such as those involved in oncogenesis.

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Section: Dna Replication Transcription Repair and Epigenetic Defectmentioning

confidence: 99%

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Cau

Navarro

Harhouri

et al. 2014

Seminars in Cell & Developmental Biology

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“…Indeed, T1L (but not T3D) altered the spicing of SRSF3, SRSF6, SRSF7, and SRSF11 (see Table S3 in the supplemental material), all of which have specialized roles in posttranscriptional regulation (30). Moreover, the top five predicted upstream regulators for altered splicing events induced by T1L (but not T3D) included SRSF1 (data not shown), another SR family member (31). Importantly, the minimal changes in splicing that occurred during T3D did not cluster in any of these categories, and there was no overlap with those obtained for T1L.…”

Section: Resultsmentioning

confidence: 94%

“…For example, SRSF1 participates in the organization of nuclear speckles and in the promotion of decay of aberrantly spliced transcripts (31,66,67), whereas SRSF2 influences transcriptional elongation of some mRNAs (68). With the exception of SRSF2, mammalian SR proteins constitutively shuttle between the nucleus and cytoplasm (26).…”

Section: Discussionmentioning

confidence: 99%

A Cytoplasmic RNA Virus Alters the Function of the Cell Splicing Protein SRSF2

Rivera-Serrano

Fritch

Scholl

et al. 2017

J Virol

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To replicate efficiently, viruses must create favorable cell conditions and overcome cell antiviral responses. We previously reported that the reovirus protein 2 from strain T1L, but not strain T3D, represses one antiviral response: alpha/beta interferon signaling. We report here that T1L, but not T3D, 2 localizes to nuclear speckles, where it forms a complex with the mRNA splicing factor SRSF2 and alters its subnuclear localization. Reovirus replicates in cytoplasmic viral factories, and there is no evidence that reovirus genomic or messenger RNAs are spliced, suggesting that T1L 2 might target splicing of cell RNAs. Indeed, RNA sequencing revealed that reovirus T1L, but not T3D, infection alters the splicing of transcripts for host genes involved in mRNA posttranscriptional modifications. Moreover, depletion of SRSF2 enhanced reovirus replication and cytopathic effect, suggesting that T1L 2 modulation of splicing benefits the virus. This provides the first report of viral antagonism of the splicing factor SRSF2 and identifies the viral protein that determines strain-specific differences in cell RNA splicing.IMPORTANCE Efficient viral replication requires that the virus create favorable cell conditions. Many viruses accomplish this by repressing specific antiviral responses. We demonstrate here that some mammalian reoviruses, RNA viruses that replicate strictly in the cytoplasm, express a protein variant that localizes to nuclear speckles, where it targets a cell mRNA splicing factor. Infection with a reovirus strain that targets this splicing factor alters splicing of cell mRNAs involved in the maturation of many other cell mRNAs. Depletion of this cell splicing factor enhances reovirus replication and cytopathic effect. Our results provide the first evidence of viral antagonism of this splicing factor and suggest that downstream consequences to the cell are global and benefit the virus.KEYWORDS RNA processing, SRSF, reovirus, splicing V iruses are obligatory intracellular pathogens that require a hospitable cell environment for their replication. However, viral infection induces cell innate responses that are antiviral. Accordingly, viruses have evolved numerous strategies to evade these responses. For example, viral infection of virtually any cell type induces a protective type I interferon (IFN-␣/␤) response, and many viruses use at least one mechanism to suppress this antiviral system (1, 2). Viral proteins that inhibit cell antiviral responses have been identified for most viruses, as have the cell proteins they target (1, 3). Not surprisingly, the most commonly identified targets are cell proteins involved in the IFN-␣/␤ response (1, 2).Mammalian reoviruses are double-stranded RNA nonenveloped viruses that replicate in membrane-associated cytoplasmic viral factories (VFs) (4, 5). Reovirus strain type 1 Lang (T1L) represses IFN-␤ signaling, while type 3 Dearing (T3D) does not (6), and this

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“…The latter binds to many long-distance locations in the X chromosome, thereby inducing its entire silencing for dosage compensation (Brown et al 1991;Brockdorff et al 1992;Herzing et al 1997). Besides epigenetic control, lncRNAs can regulate transcription, alternative splicing, RNA translation, and organize important structures for RNA processing such as nuclear speckles (Tripathi et al 2010(Tripathi et al , 2012Zong et al 2011;Yoon et al 2013). Figure 1 summarizes the different molecular and cellular functions of lncRNAs.…”

Section: Introductionmentioning

confidence: 99%

Databases for lncRNAs: a comparative evaluation of emerging tools

Fritah

Niclou

Azuaje

2014

RNA

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The vast majority of the human transcriptome does not code for proteins. Advances in transcriptome arrays and deep sequencing are giving rise to a fast accumulation of large data sets, particularly of long noncoding RNAs (lncRNAs). Although it is clear that individual lncRNAs may play important and diverse biological roles, there is a large gap between the number of existing lncRNAs and their known relation to molecular/cellular function. This and related information have recently been gathered in several databases dedicated to lncRNA research. Here, we review the content of general and more specialized databases on lncRNAs. We evaluate these resources in terms of the quality of annotations, the reporting of validated or predicted molecular associations, and their integration with other resources and computational analysis tools. We illustrate our findings using known and novel cancer-related lncRNAs. Finally, we discuss limitations and highlight potential future directions for these databases to help delineating functions associated with lncRNAs.

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SRSF1 regulates the assembly of pre-mRNA processing factors in nuclear speckles

Cited by 108 publications

References 72 publications

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

A Cytoplasmic RNA Virus Alters the Function of the Cell Splicing Protein SRSF2

Databases for lncRNAs: a comparative evaluation of emerging tools

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