FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2

Schwartz, Jacob C.; Ebmeier, Christopher C.; Podell, Elaine R.; Heimiller, Joseph; Taatjes, Dylan J.; Cech, Thomas R.

doi:10.1101/gad.204602.112

Cited by 203 publications

(316 citation statements)

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“…These effects could reflect mechanistically changes in the activity of FUS-interacting proteins; e.g., transcription factors TFIID and RNAP II, splicing factor SRSF10 (Tan and Manley 2009), and/or decreased occupancy on target RNA/DNA sequences (Ishigaki et al 2012;Rogelj et al 2012). Indeed, changes in phosphorylation of the RNAP II large subunit regulatory domain, the C-terminal domain (CTD), have been reported in both FUS knockdown cells and ALS patient fibroblasts, leading to global changes in gene expression (Schwartz et al 2012; and consistent with the known roles of the CTD in transcription and mRNA processing (for review, see Hsin and Manley 2012). However, changes in gene expression resulting solely from reduced levels of nuclear FUS are insufficient to explain fully changes that occur in the presence of ALS mutant FUS.…”

Section: Discussionmentioning

confidence: 99%

“…TET proteins share similar domain organization and copurify or interact with transcription factors (TFIID and RNA polymerase II [RNAP II]) (Bertolotti et al 1996;Law et al 2006;Kwon et al 2013) on the one hand and the spliceosome and SR protein-splicing factors (Yang et al 1998;Rappsilber et al 2002;Zhou et al 2002;Meissner et al 2003;Leichter et al 2011) on the other, suggesting possible roles in coupling transcription and splicing. Considerable evidence implicates TET proteins in splicing control in vivo (Paronetto et al 2011;Blechingberg et al 2012), and FUS was shown to enhance RNAP II transcription while repressing RNAP III transcription in vitro (Tan and Manley 2010) and increase RNAP II phosphorylation, and thereby transcription elongation, in vivo (Schwartz et al 2012). However, the relationship between FUS protein function and ALS pathology has yet to be elucidated.…”

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confidence: 99%

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ALS mutations in TLS/FUS disrupt target gene expression

Coady

Manley

2015

Genes Dev.

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Amyotrophic lateral sclerosis (ALS) is caused by mutations in a number of genes, including the gene encoding the RNA/DNA-binding protein translocated in liposarcoma or fused in sarcoma (TLS/FUS or FUS). Previously, we identified a number of FUS target genes, among them MECP2. To investigate how ALS mutations in FUS might impact target gene expression, we examined the effects of several FUS derivatives harboring ALS mutations, such as R521C (FUS C ), on MECP2 expression in transfected human U87 cells. Strikingly, FUS C and other mutants not only altered MECP2 alternative splicing but also markedly increased mRNA abundance, which we show resulted from sharply elevated stability. Paradoxically, however, MeCP2 protein levels were significantly reduced in cells expressing ALS mutant derivatives. Providing a parsimonious explanation for these results, biochemical fractionation and in vivo localization studies revealed that MECP2 mRNA colocalized with cytoplasmic FUS C in insoluble aggregates, which are characteristic of ALS mutant proteins. Together, our results establish that ALS mutations in FUS can strongly impact target gene expression, reflecting a dominant effect of FUS-containing aggregates.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

ALS mutations in TLS/FUS disrupt target gene expression

Coady

Manley

2015

Genes Dev.

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“…In keeping with the latter, FUS functions in both the soluble nuclear and chromatin fractions. In the chromatin fraction, it binds to the C-terminal domain of RNA Pol II and modulates its phosphorylation on Serine 2, which helps to regulate the transcription of certain genes (20,21). FUS also colocalizes with active (serine 2 phosphorylated) RNA Pol II in undamaged cells (22).…”

Section: Depletion Of Fus and Tdp43 Leads To Excessive Transcription mentioning

confidence: 99%

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Hill

Mordes

Cameron

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

119

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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loopassociated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis.A myotrophic lateral sclerosis (ALS) is a disease of both upper and lower motor neuron dysfunction that leads to progressive paralysis and eventually death due to respiratory failure. No single model of ALS disease pathogenesis has been revealed; however, multiple disease-associated genes are known (1). The variation in function of these genes suggests that there may be multiple ALS molecular subtypes. That said, the familial ALS gene product list is also enriched in protein groups with related functions.Mutations in multiple RNA processing genes, including FUS (FUS RNA-binding protein), TDP43 (TAR DNA-binding protein), SETX (senataxin), TAF15 (TATA box-binding protein-associated factor 15), EWSR1 (EWS RNA-binding protein 1), HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1), and HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1), among others, give rise to familial ALS (fALS) (1). FUS and TDP43 are currently the best studied, given that mutations in these genes lead to classic histologic findings in ALS neural tissue and that similar histologic findings can be found in neural tissue of sporadic ALS cases (2). At autopsy, cytoplasmic TDP43 inclusions are found in ALS motor neurons from patients with (i) TDP43 mutations and (ii) sporadic ALS (i.e., patients with no FUS, TDP43, or other known pathogenic mutation) (2). They are also present in neurons in various parts of the brains of patients with either sporadic or familial versions of the ALS-related disorder, fronto-temporal lobar dementia (FTLD) (2). At autopsy, FUS inclusions were detected in the cytoplasm of motor neurons of FUS mutation-bearing fALS patients and in the cytoplasm of neurons in various regions of the brain in some FTLD patients (2).FUS and TDP43 exhibit a wide range of functions, most of which involv...

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“…FUS has been implicated in transcriptional and posttranscriptional regulation of gene expression (21)(22)(23)(24)(25)(26). We therefore asked whether changes in gene-expression patterns in CAG-FUS WT and CAG-FUS R521G mice explain both the similarities and differences in the behavioral and cellular phenotypes of the wild-type and mutant transgenic mice.…”

Section: Development Of Cre-inducible Transgenic Mice Globally Overexmentioning

confidence: 99%

Activity-dependent FUS dysregulation disrupts synaptic homeostasis

Sephton

Tang

Kulkarni

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

122

123

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The RNA-binding protein fused-in-sarcoma (FUS) has been associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative disorders that share similar clinical and pathological features. Both missense mutations and overexpression of wild-type FUS protein can be pathogenic in human patients. To study the molecular and cellular basis by which FUS mutations and overexpression cause disease, we generated novel transgenic mice globally expressing low levels of human wild-type protein (FUS WT ) and a pathological mutation (FUS R521G A myotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons, leading to muscle weakness, paralysis, and death within 3-5 y of onset. Interestingly, ∼10-15% of ALS patients have clinical features of frontotemporal lobar degeneration (FTLD), marked by a decline in decision-making, behavioral control, emotion, and language, and as many as half have mild-to-moderate cognitive or behavioral abnormalities (1). FTLD comprises a group of heterogeneous diseases characterized by progressive neurodegeneration of the frontal and temporal lobes and clinically by frontotemporal dementia (FTD) with or without motor neuron disease. There is no cure or effective therapy for those who suffer from ALS or FTLD, and the mechanisms by which these diseases occur are not well understood.The clinical, pathological, and genetic overlap between ALS and FTLD suggests that there are mechanisms shared by these diseases. The RNA-binding proteins fused in sarcoma (FUS) and transactive response DNA-binding protein-43 (TDP-43) are the major protein components of inclusions that are characteristic of ALS and FTLD-U (FTLD with ubiquitinated inclusions) (2). More than 50 genetic FUS mutations have been identified in these related neurodegenerative disorders (3). Similarly, more than 40 dominant mutations in the TDP-43 gene have been linked to ALS cases and, to a lesser extent, to FTLD (4). The identification of mutations in the FUS and TDP-43 genes has provided insights for uncovering the disease mechanisms for ALS and FTLD.FUS is a ubiquitously expressed RNA-binding protein that exists in dynamic ribonucleoprotein complexes involved in pre-mRNA splicing, mRNA stability, and mRNA transport. FUS is a member of the FET family of proteins that bind RNAs (5) and contains an RNA recognition motif, three arginine-glycine-glycine (RGG) boxes, and a zinc finger (ZnF) (6). RGG2-ZnF-RGG3 is the major RNA-binding domain, which has a preference for GUrich sequences (7,8). The N terminus of FUS contains a lowcomplexity sequence domain involved in RNA granule formation (9). Nucleocytoplasmic shuttling of FUS occurs by a nonclassical proline-tyrosine nuclear localization signal (PY-NLS) and a nuclear export signal (NES) (10). Methylation of the C-terminal RGG3 domain of FUS is necessary for transportin 1 interaction and nuclear localization (11).The majority of clinical ALS/FTLD-associated FUS mutations occur in its C-terminal PY-NLS seque...

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FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2

Cited by 203 publications

References 23 publications

ALS mutations in TLS/FUS disrupt target gene expression

ALS mutations in TLS/FUS disrupt target gene expression

Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage

Activity-dependent FUS dysregulation disrupts synaptic homeostasis

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