FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP

Yu, Yanke; Reed, Robin

doi:10.1073/pnas.1506282112

Cited by 97 publications

(90 citation statements)

References 43 publications

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“…16 Recent in vitro analysis using the HeLa cell nuclear extracts has revealed that FUS couples transcription with splicing by mediating an association between RNAP II and U1 snRNP. 61 FUS may be an intermediate factor that links transcription and splicing (Figure 3). …”

Section: Alternative Splicingmentioning

confidence: 99%

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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Section: Alternative Splicingmentioning

confidence: 99%

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

2016

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“…FUS is a DNA- and RNA-binding protein with evidence for functions in DNA repair, transcriptional regulation, alternative splicing regulation, RNA localization, and association with stress granules (Sama et al, 2014). FUS has also been shown to couple transcription to alternative splicing by interacting with both RNA polymerase II and U1 snRNP (Yu and Reed, 2015). Homozygous knockout of Fus produces perinatal lethality in inbred mouse lines (Hicks et al, 2000).…”

Section: Fus and Tdp-43 In Alsmentioning

confidence: 99%

Roles for RNA-binding proteins in development and disease

2016

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RNA-binding protein activities are highly regulated through protein levels, intracellular localization, and post-translation modifications. During development, mRNA processing of specific gene sets is regulated through manipulation of functional RNA-binding protein activities. The impact of altered RNA-binding protein activities also affects human diseases in which there are either a gain-of-function or loss-of-function causes pathogenesis. We will discuss RNA-binding proteins and their normal developmental RNA metabolism and contrast how their function is disrupted in disease.

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“…In addition to a direct alteration on this process, ALS-related mutations may affect also the network of protein-protein interaction of FUS and TDP-43 with other splicing factors. Indeed, FUS interacts with both RNA polymerase II and the small nuclear ribonucleoprotein complex snRNP U1, thus suggesting that it might have a role in coupling transcription to splicing (143). Moreover, FUS and TDP-43 interact with the SMN complex, which is essential for spliceosome assembly (132,140) and mutant FUS sequesters both SMN and snRNPs in protein aggregates in the cytoplasm, leading to alteration in the alternative splicing process (45,142).…”

Section: Tdp-43 and Fus: Rna Dys-metabolism As A Novel Player In Alsmentioning

confidence: 99%

Old versus New Mechanisms in the Pathogenesis of ALS

2016

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Amyotrophic Lateral Sclerosis (ALS) is recognized as a very complex disease. As we have learned in the past 20 years from studies in patients and in models based on the expression of mutant SOD1, ALS is not a purely motor neuron disease as previously thought. While undoubtedly motor neurons are lost in patients, a number of alterations in those cell-types that interact functionally with motor neurons (astrocytes, microglia, muscle fibers, oligodendrocytes) take place even long before onset of symptoms. At the same time, disturbance of several, only partly inter-related physiological functions play some role in the onset and progression of the disease. Traditionally, mitochondrial damage and oxidative stress, excitotoxicity, neuroinflammation, altered axonal transport, ER stress, protein aggregation and defective removal of toxic proteins have been considered as key factors in the pathogenesis of ALS, with the relatively recent addition of disturbances in RNA metabolism. This complexity makes the search for an effective treatment extremely difficult and prompts further studies to reveal other possible, previously unappreciated aspects of the pathogenesis of ALS. In this review, we focus on previous knowledge on ALS mechanisms as well as new facets emerging from studies on genetic ALS patients and models that may both provide precious information for a novel therapeutic approach.

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FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP

Cited by 97 publications

References 43 publications

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

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

Roles for RNA-binding proteins in development and disease

Old versus New Mechanisms in the Pathogenesis of ALS

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