Position-specific binding of FUS to nascent RNA regulates mRNA length

Matsubara, Akio; Takeda, Jun‐ichi; Okuno, Tatsuya; Okamoto, Takahiro; Ohkawara, Bisei; Ito, Mikako; Ishigaki, Shinsuke; Sobue, Gen; Ohno, Kinji

doi:10.1101/gad.255737.114

Cited by 107 publications

(159 citation statements)

References 55 publications

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“…FUS is a member of the TET/ FET family of proteins, which includes two other similar proteins, EWS and TAF-15; is ubiquitously expressed; and has many proposed cellular functions, ranging from transcription to RNA processing to DNA damage repair (Tan and Manley 2009;Wang et al 2013). The protein's ability to shuttle between the nucleus and cytoplasm might have important consequences for synaptic mRNA transport (Fujii et al 2005;Masuda et al 2015). Structurally, FUS consists of an N-terminal domain comprised of a QGSY region and the first of three RGG repeat regions, and an RRM and zinc finger motif account for its ability to bind nucleic acids.…”

Section: Fusmentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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Neurodegeneration is a leading cause of death in the developed world and a natural, albeit unfortunate, consequence of longer-lived populations. Despite great demand for therapeutic intervention, it is often the case that these diseases are insufficiently understood at the basic molecular level. What little is known has prompted much hopeful speculation about a generalized mechanistic thread that ties these disparate conditions together at the subcellular level and can be exploited for broad curative benefit. In this review, we discuss a prominent theory supported by genetic and pathological changes in an array of neurodegenerative diseases: that neurons are particularly vulnerable to disruption of RNA-binding protein dosage and dynamics. Here we synthesize the progress made at the clinical, genetic, and biophysical levels and conclude that this perspective offers the most parsimonious explanation for these mysterious diseases. Where appropriate, we highlight the reciprocal benefits of cross-disciplinary collaboration between disease specialists and RNA biologists as we envision a future in which neurodegeneration declines and our understanding of the broad importance of RNA processing deepens.

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Section: Fusmentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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“…39,47 A similar shift in RNAP II distribution toward TSS by Fus knockdown was also observed in our RNAP II ChIP-seq analysis of N2A cells. 16 These findings indicate that FUS regulates transcriptional activity of RNAP II through direct interactions with CTD. Furthermore, our comprehensive analysis of CLIP-seq, RNAP II ChIP-seq, and Nascent-seq revealed that FUS-RNA interaction fine-tunes local transcription via RNAP II.…”

Section: Relationship Between Rnap II and Fusmentioning

confidence: 96%

“…19,22 Gene ontology analysis has shown that genes highly covered with FUS-CLIP tags are involved in neuron-specific functions, such as synaptic control, cell adhesion, and neuronal projection and recognition processes. 23 Analyses of CLIP-seq have revealed that FUS recognizes GU-rich motifs in vivo, 16,19,22 which is similar to the GGUG motif identified using in vitro SELEX analysis. 26 In addition, NMR analysis showed that the zinc-finger domain of FUS directly binds to GGUG-containing RNA.…”

Section: Advanced Review Wireswileycom/rnamentioning

confidence: 96%

“…16 We detected 36,353 transcription start sites (TSSs), 3386 alternative splice sites, and 46,081 polyA sites in these cells, and identified that FUS-CLIP clusters were enriched around all three sites. Enrichment of FUS binding around alternative RNA processing sites has also been detected in other studies, 18,19,22 indicating the importance of FUS-RNA interaction in the regulation of alternative RNA processing events.…”

Section: Advanced Review Wireswileycom/rnamentioning

confidence: 97%

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FUS‐mediated regulation of alternative RNA processing in neurons: insights from global transcriptome analysis

2016

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Fused in sarcoma (FUS) is an RNA-binding protein that is causally associated with oncogenesis and neurodegeneration. Recently, the role of FUS in neurodegeneration has been extensively studied, because mutations in FUS are associated with amyotrophic lateral sclerosis (ALS), and the FUS protein has been identified as a major component of intracellular inclusions in neurodegenerative disorders including ALS and frontotemporal lobar degeneration. FUS is a key molecule in transcriptional regulation and RNA processing including processes such as pre-messenger RNA (mRNA) splicing and polyadenylation. Interaction of FUS with various components of the transcription machinery, spliceosome, and the 3'-end processing machinery has been identified. Furthermore, recent advances in high-throughput transcriptomic profiling approaches have enabled us to determine the mechanisms of FUS-dependent RNA processing networks at a cellular level. These analyses have revealed that depletion of FUS in neuronal cells affects alternative splicing and alternative polyadenylation of thousands of mRNAs. Gene ontology analysis has suggested that FUS-modulated genes are implicated in neuronal functions and development. CLIP-seq of FUS has shown that FUS is frequently clustered around these alternative sites of nascent RNA. ChIP-seq of RNA polymerase II (RNAP II) has demonstrated that an interaction between FUS and nascent RNA downregulates local transcriptional activity of RNAP II, which is critically involved in RNA processing. Both alternative splicing and alternative polyadenylation are fundamental processes by which cells expand their transcriptomic diversity, and are particularly essential in the nervous system. Dependence of transcriptomic diversity on FUS makes the nervous system vulnerable to neurodegeneration, when FUS is functionally compromised. WIREs RNA 2016, 7:330-340. doi: 10.1002/wrna.1338 For further resources related to this article, please visit the WIREs website.

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“…When an APA site is upstream of an FUS-binding site, FUS enhances polyadenylation at that site by recruiting CPSF. However, when an APA site is found downstream from an FUS-binding site, polyadenylation is not activated (Masuda et al 2015). Adding further complexity into regulation mediated by RBP-and APA-based gene expression, multiple RBPs can bind the same mRNA as was exemplified by the PTGS2 (prostaglandin-endoperoxide synthase 2, synonym COX2) USE, where several RBPs including PSF (polypyrimidine tract-binding protein-associated splicing factor), SRSF11 (serine/arginine-rich splicing factor 11, p54), hnRNP I (synonyms PTBP1 (polypyrimidine tract-binding protein 1, PTB), and U1A proteins bind to regulate APA (Hall-Pogar et al 2007).…”

Section: Role Of Rbps In Apa Decisionsmentioning

confidence: 99%

Alternative polyadenylation and RNA-binding proteins

Erson-Bensan

2016

Journal of Molecular Endocrinology

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Our understanding of the extent of microRNA-based gene regulation has expanded in an impressive pace over the past decade. Now, we are beginning to better appreciate the role of 3′-UTR (untranslated region) cis-elements which harbor not only microRNA but also RNA-binding protein (RBP) binding sites that have significant effect on the stability and translational rate of mRNAs. To add further complexity, alternative polyadenylation (APA) emerges as a widespread mechanism to regulate gene expression by producing shorter or longer mRNA isoforms that differ in the length of their 3′-UTRs or even coding sequences. Resulting shorter mRNA isoforms generally lack cis-elements where trans-acting factors bind, and hence are differentially regulated compared with the longer isoforms. This review focuses on the RBPs involved in APA regulation and their action mechanisms on APA-generated isoforms. A better understanding of the complex interactions between APA and RBPs is promising for mechanistic and clinical implications including biomarker discovery and new therapeutic approaches.

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Position-specific binding of FUS to nascent RNA regulates mRNA length

Cited by 107 publications

References 55 publications

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

FUS‐mediated regulation of alternative RNA processing in neurons: insights from global transcriptome analysis

Alternative polyadenylation and RNA-binding proteins

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