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FLASH GENE
Symbol FUS contributors: mct/pgu - updated : 20-04-2017
HGNC name fused in sarcoma
HGNC id 4010
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N terminal SER, TYR, GLU, GLY rich domain, with transcriptional activating properties
  • a RNA binding domain
  • C2-C2 finger motif in the central region
  • a non-classical proline/tyrosine–nuclear localization signal (PY-NLS) in the C-terminus, necessary for nuclear import (AAs 514-526), and capable of binding DNA, RNA and splicing factors , that bind the import-karyopherin, karyopherinbeta2 (TNPO1) in a RAN-sensitive manner
    • HOMOLOGY
    intraspecies homolog to EWS1, highly
    Homologene
    FAMILY
  • RRM TET family
    • CATEGORY RNA associated
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    text
  • normally located predominantly in the nucleus but the mutant forms accumulated in the cytoplasm of neurons )
  • also present in the cytosol where they are involved in diverse aspects of RNA metabolism, regulating the spatiotemporal fate of mRNA, i.e. subcellular localization, translation or degradation (Lagier-tourenne 2010)
  • mutations in the C-terminus of FUS show neuronal cytoplasmic FUS-positive inclusions, whereas in healthy controls, FUS is predominantly nuclear (but cytosolic FUS may accumulate during ageing)
  • FUS is normally located in the nucleus but in ALS, it translocates to the cytoplasm and misfolds, forming inclusions
    • basic FUNCTION
  • regulator of BCR/ABL-mediated leukemogenesis
  • implicated in mRNA export and mRNA transport to neuronal dendrites
  • may play a role in maintenance of genomic integrity
  • nucleoprotein that functions in DNA and RNA metabolism and implicated in tumorigenesis
  • sequestration of FUS to polyQ aggregates may play a role in diverse pathological changes in the brains of patients with polyQ disease
  • fusion protein caused by chromosomal translocations in human cancers
  • with TARDBP may play roles in micro-RNA (miRNA) processing
  • TARDBP and FUS implicated in neurodegeneration through errors in multiple steps of RNA processing
  • with TARDBP operate together in a common biochemical pathway
  • TARDBP and FUS are both RNA/DNA-binding proteins with striking structural and functional similarities
  • regulates expression of specific target genes, likely via recognition of specific single-stranded DNA sequences located within their promoter regions
  • is an unusual transcriptional regulator with the potential to activate or repress target genes via specific ssDNA sequences
  • may negatively regulate cell-cycle progression both through repressing transcription of RAS family genes and through alternative splicing that produces isoforms that delay cell-cycle progression
  • role in regulating processes as diverse as transcription, cell-cycle progress, DNA repair and genomic stability, and neurodegeneration
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA RNA binding protein (FUSIP/TASR1, SFRS2/SR351)
    small molecule other,
  • associated with neuronal intranuclear inclusions of Huntington disease brain
    • protein
  • interacting with serine arginine proteins involved in RNA splicing
  • interacts with several nuclear hormone receptors and with gene-specific transcription factors such as Spi-1/PU.1 or NF-KB
  • plays a significant role in expression of a number of RNAP II transcribed genes
  • FUS/TLS was found associated with TARDBP, association that is strongly enhanced by ALS-linked mutations
  • interaction between the FUS N-terminal and the cytolinker plectin (PLEC is important for normal FUS localization and function)
  • strong binding to the INTS3 gene
  • MAPT mRNA is a physiological splicing target of FUS
  • FUS bind the import-karyopherin, karyopherinbeta2 (TNPO1) in a RAN-sensitive manner, and TNPO1 plays likely a major role in nuclear localization of FUS
  • ATXN2 associates preferentially with pathological forms of FUS
  • interactions between FUS and proteins involved in neurodegenerative diseases and/or ubiquitin proteasome pathway, such as VCP, SFPQ, UBA1, and 26S proteosome non-ATPase regulatory subunit 12 (PSMD12)
  • FUS interacts with a mitochondrial chaperonin, HSPD1, and FUS translocation to mitochondria is, at least in part, mediated by HSPD1
  • FUS co-localises with the mitochondrial tethering protein Syntaphilin (SNPH), and mutations in FUS affect this relationship
    • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) FUS , AMLT1 , ALS6 , ETM4
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral   translocation    
    rearranged in myxoid liposarcoma with translocation t(12;16) and in myeloid leukemia with translocation t(16;21)(q13;p11)
    tumoral fusion      
    fused with ATF1 in t (12;16)(q13;p11) in angiomatoid fibrous histiocytomas and with DDIT3 in myxoid liposarcoma
    tumoral fusion      
    fused with ERG in t(16;21)(p11;q22)in Ewing sarcoma
    tumoral fusion      
    with CREB3L2 in t(7;16) (q33;p11 in fibromyxoid sarcoma, low-grade
    constitutional germinal mutation      
    in ALS6, amyotrophic lateral sclerosis (R521G missense mutation in FUS/TLS led to aberrant trafficking with subsequent cytoplasmic retention of the mutant protein)
    tumoral     --over  
    in liposarcoma
    Susceptibility to essential tremor
    Variant & Polymorphism other
  • nonsense mutation (c.868C>T) associated to essential tremor
    • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
    major components of nuclear polyQ aggregate-interacting proteins in a Huntington disease cell model and was also associated with neuronal intranuclear inclusions of R6/2 mice