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FLASH GENE

Symbol

FUS

contributors: mct/pgu - updated : 20-04-2017

HGNC name	fused in sarcoma
HGNC id	4010

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	11.65 kb     15 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
text structure	the promoter and N-terminal part of FUS/TLS is translocated to the C-terminal domain of various DNA-binding transcription factors conferring a strong transcriptional activation domain to the fusion proteins

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004960 15 - 5119 NP_004951 - 526 - 2009 19251627 NM_001170634 - - 5116 NP_001164105 - 525 - 2009 19251627 NM_001170937 - - 5107 NP_001164408 - 522 - 2009 19251627

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine small intestine     highly Lymphoid/Immune lymph node       highly Reproductive female system ovary     highly   female system uterus     highly Urinary kidney       highly

cell lineage

cell lines

fluid/secretion

at STAGE

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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