FUS (gene)

FUS
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 2LA6, 2LCW, 4FDD, 4FQ3
Identifiers
Aliases	FUS, ALS6, ETM4, FUS1, HNRNPP2, POMP75, TLS, FUS RNA binding protein
External IDs	GeneCards: FUS
Gene ontology Molecular function • nucleotide binding • DNA binding • transcription coactivator activity • zinc ion binding • metal ion binding • retinoid X receptor binding • thyroid hormone receptor binding • myosin V binding • protein binding • RNA binding • identical protein binding • nucleic acid binding • poly(A) RNA binding • ionotropic glutamate receptor binding • estrogen receptor binding Cellular component • cytoplasm • polysome • perikaryon • dendritic spine • nucleoplasm • neuronal cell body • dendrite • dendritic spine head • perinuclear region of cytoplasm • nucleus Biological process • cellular response to calcium ion • mRNA splicing, via spliceosome • regulation of nucleic acid-templated transcription Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2521	n/a
Ensembl	ENSG00000089280	n/a
UniProt	P35637	n/a
RefSeq (mRNA)	NM_001010850 NM_001170634 NM_001170937 NM_004960	n/a
RefSeq (protein)	NP_001164105.1 NP_004951.1	n/a
Location (UCSC)	Chr 16: 31.18 – 31.19 Mb	n/a
PubMed search	[1]	n/a
Wikidata

RNA-binding protein FUS/TLS (Fused in Sarcoma/Translocated in Sarcoma) is a protein that in humans is encoded by the FUS gene.^{[2][3][4][5][6][7]}

Structure and function

The N-terminal end of FUS appears to be involved in transcriptional activation, while the C-terminal end is involved in protein and RNA binding. In addition recognition sites for the transcription factors AP2, GCF, Sp1 have been identified in FUS.^[8]

FUS/TLS is a member of the TET protein family that also includes the EWS protein, the TATA-binding protein (TBP)-associated factor (TAFII68/TAF15) and the Drosophila cabeza/SARF protein.^[9][10]

FUS/TLS, EWS and TAFII68/TAF15 have a similar structure characterised by an N-terminal QGSY-rich region, a highly conserved RNA recognition motif (RRM), multiple RGG repeats, which are extensively dimethylated at arginine residues^[11] and a C-terminal zinc finger motif.^{[4][6][9][12]}

Discovery

FUS/TLS was initially identified as a fusion protein (FUS-CHOP) caused by chromosomal translocations in human cancers especially liposarcomas.^[3][6] In these instances, the promoter and N-terminal part of FUS/TLS is translocated to the C-terminal domain of various DNA-binding transcription factors (eg CHOP) conferring a strong transcriptional activation domain to the fusion proteins.^[10][13]

FUS/TLS was independently identified as the hnRNP P2 protein, a subunit of a complex involved in maturation of pre-mRNA.^[14]

Function

Consistently, in vitro studies have shown that FUS/TLS binds RNA, single-stranded DNA and (with lower affinity) double-stranded DNA.^{[4][6][15][16][17][18]} The sequence specificity of FUS/TLS binding to RNA or DNA has not been well established; however, using in vitro selection (SELEX), a common GGUG motif has been identified in approximately half of the RNA sequences bound by FUS/TLS.^[19] A later proposal was that the GGUG motif is recognised by the zinc finger domain and not the RRM (80). Additionally, FUS/TLS has been found to bind a relatively long region in the 3′ untranslated region (UTR) of the actin-stabilising protein Nd1-L mRNA, suggesting that rather than recognising specific short sequences, FUS/TLS interacts with multiple RNA-binding motifs or recognises secondary conformations.^[20] FUS/TLS has also been proposed to bind human telomeric RNA (UUAGGG)4 and single-stranded human telomeric DNA in vitro.^[21]

Beyond nucleic acid binding, FUS/TLS was also found to associate with both general and more specialized protein factors to influence the initiation of transcription.^[22] Indeed, FUS/TLS interacts with several nuclear receptors.^[23] and with gene-specific transcription factors such as Spi-1/PU.1.^[24] or NF-κB.^[25] It also associates with the general transcriptional machinery and may influence transcription initiation and promoter selection by interacting with RNA polymerase II and the TFIID complex.^[26][27][28] Recently, FUS/TLS was also shown to repress the transcription of RNAP III genes and to co-immunoprecipitate with TBP and the TFIIIB complex.^[29]

Clinical significance

FUS gene rearrangement has been implicated in the pathogenesis of both myxoid liposarcoma and low grade fibromyxoid sarcoma.

In 2009 two separate research groups analysed 26 unrelated families who presented with a type6 ALS phenotype, and found 14 mutations in the FUS gene.^[30][31]

Subsequently, FUS has also emerged as a significant disease protein in a subgroup of frontotemporal lobar dementias (FTLDs), previously characterized by immunoreactivity of the neuronal inclusions for ubiquitin, but not for TDP-43 or tau with a proportion of the inclusions also containing a-internexin in a further subgroup known as neuronal intermediate filament inclusion disease (NIFID). The disease entities which are now considered subtypes of FTLD-FUS are atypical frontotemporal lobar degeneration with ubiquitinated inclusions (aFTLD-U), NIFID (otherwise known as neurofilament inclusion body disease) and basophilic inclusion body disease (BIBD), which together with ALS-FUS comprise the FUS-opathies.^{[32][33][34][35]}

FTLD is the pathological term for the clinical syndrome of frontotemporal dementia (FTD). FTD differs from the more common Alzheimer's dementia in that memory is relatively well preserved, instead the disease presents with a more temporal-lobe phenotype. Behavioural variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia (PNFA) and semantic dementia (SD) are the three best-characterised clinical presentations. FUS positive FTLD tends to present clinically as a bvFTD but the correlation between underlying pathology and clinical presentation is not perfect.

Interactions

FUS has been shown to interact with:

• FUSIP1/SRSF10^[28]
• ILF3,^[36]
• PRMT1,^[37][38][39]
• RELA,^[25]
• SPI1,^[24] and
• TNPO1.^[40][41]

References

Further reading