FUS

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For other uses, see Fus.
Fused in sarcoma
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols FUS ; ALS6; ETM4; FUS1; HNRNPP2; POMP75; TLS
External IDs OMIM137070 MGI1353633 HomoloGene3639 GeneCards: FUS Gene
RNA expression pattern
PBB GE FUS 200959 at tn.png
PBB GE FUS 217370 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2521 233908
Ensembl ENSG00000089280 ENSMUSG00000030795
UniProt P35637 P56959
RefSeq (mRNA) NM_001010850 NM_139149
RefSeq (protein) NP_001164105 NP_631888
Location (UCSC) Chr 16:
31.19 – 31.2 Mb
Chr 7:
127.97 – 127.98 Mb
PubMed search [1] [2]

RNA-binding protein FUS/TLS (Fused in Sarcoma/Translocated in Sarcoma) is a protein that in humans is encoded by the FUS gene.[1][2][3][4][5][6]

Structure and Function[edit]

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.[7]

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.[8][9]

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[10] and a C-terminal zinc finger motif.[5][3][8][11] FUS/TLS was initially identified as a fusion protein caused by chromosomal translocations in human cancers.[5][2] 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 conferring a strong transcriptional activation domain to the fusion proteins.[9][12] FUS/TLS was independently identified as the hnRNP P2 protein, a subunit of a complex involved in maturation of pre-mRNA.[13] Consistently, in vitro studies have shown that FUS/TLS binds RNA, single-stranded DNA and (with lower affinity) double-stranded DNA.[5][3][14][15][16][17] 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.[18] 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.[19] FUS/TLS has also been proposed to bind human telomeric RNA (UUAGGG)4 and single-stranded human telomeric DNA in vitro.[20]

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.[21] Indeed, FUS/TLS interacts with several nuclear receptors.[22] and with gene-specific transcription factors such as Spi-1/PU.1.[23] or NF-κB.[24] 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.[25][26][27] Recently, FUS/TLS was also shown to repress the transcription of RNAP III genes and to co-immunoprecipitate with TBP and the TFIIIB complex.[28]

Clinical significance[edit]

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.[29][30] 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.[31][32][33][34]

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[edit]

FUS has been shown to interact with:

References[edit]

  1. ^ Eneroth M, Mandahl N, Heim S, Willen H, Rydholm A, Alberts KA, Mitelman F (Aug 1990). "Localization of the chromosomal breakpoints of the t(12;16) in liposarcoma to subbands 12q13.3 and 16p11.2". Cancer Genet Cytogenet 48 (1): 101–7. doi:10.1016/0165-4608(90)90222-V. PMID 2372777. 
  2. ^ a b Rabbitts TH, Forster A, Larson R, Nathan P (Sep 1993). "Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma". Nat Genet 4 (2): 175–80. doi:10.1038/ng0693-175. PMID 7503811. 
  3. ^ a b c Prasad DD, Ouchida M, Lee L, Rao VN, Reddy ES (December 1994). "TLS/FUS fusion domain of TLS/FUS-erg chimeric protein resulting from the t(16;21) chromosomal translocation in human myeloid leukemia functions as a transcriptional activation domain". Oncogene 9 (12): 3717–29. PMID 7970732. 
  4. ^ "Entrez Gene: FUS fusion (involved in t(12;16) in malignant liposarcoma)". 
  5. ^ a b c d Crozat A, Aman P, Mandahl N, Ron D (June 1993). "Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma". Nature 363 (6430): 640–4. doi:10.1038/363640a0. PMID 8510758. 
  6. ^ Mrózek K, Karakousis CP, Bloomfield CD (April 1993). "Chromosome 12 breakpoints are cytogenetically different in benign and malignant lipogenic tumors: localization of breakpoints in lipoma to 12q15 and in myxoid liposarcoma to 12q13.3". Cancer Res. 53 (7): 1670–5. PMID 8453640. 
  7. ^ Aman P, Panagopoulos I, Lassen C, Fioretos T, Mencinger M, Toresson H, Höglund M, Forster A, Rabbitts TH, Ron D, Mandahl N, Mitelman F (October 1996). "Expression patterns of the human sarcoma-associated genes FUS and EWS and the genomic structure of FUS". Genomics 37 (1): 1–8. doi:10.1006/geno.1996.0513. PMID 8921363. 
  8. ^ a b Morohoshi F, Ootsuka Y, Arai K, Ichikawa H, Mitani S, Munakata N, Ohki M (October 1998). "Genomic structure of the human RBP56/hTAFII68 and FUS/TLS genes". Gene 221 (2): 191–8. doi:10.1016/S0378-1119(98)00463-6. PMID 9795213. 
  9. ^ a b Bertolotti A, Bell B, Tora L (December 1999). "The N-terminal domain of human TAFII68 displays transactivation and oncogenic properties". Oncogene 18 (56): 8000–10. doi:10.1038/sj.onc.1203207. PMID 10637511. 
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  11. ^ Iko Y, Kodama TS, Kasai N, Oyama T, Morita EH, Muto T, Okumura M, Fujii R, Takumi T, Tate S, Morikawa K (October 2004). "Domain architectures and characterization of an RNA-binding protein, TLS". J. Biol. Chem. 279 (43): 44834–40. doi:10.1074/jbc.M408552200. PMID 15299008. 
  12. ^ Zinszner H, Albalat R, Ron D (November 1994). "A novel effector domain from the RNA-binding protein TLS or EWS is required for oncogenic transformation by CHOP". Genes Dev. 8 (21): 2513–26. doi:10.1101/gad.8.21.2513. PMID 7958914. 
  13. ^ Calvio C, Neubauer G, Mann M, Lamond AI (September 1995). "Identification of hnRNP P2 as TLS/FUS using electrospray mass spectrometry". RNA 1 (7): 724–33. PMC 1369314. PMID 7585257. 
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  16. ^ Baechtold H, Kuroda M, Sok J, Ron D, Lopez BS, Akhmedov AT (November 1999). "Human 75-kDa DNA-pairing protein is identical to the pro-oncoprotein TLS/FUS and is able to promote D-loop formation". J. Biol. Chem. 274 (48): 34337–42. doi:10.1074/jbc.274.48.34337. PMID 10567410. 
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  18. ^ Lerga A, Hallier M, Delva L, Orvain C, Gallais I, Marie J, Moreau-Gachelin F (March 2001). "Identification of an RNA binding specificity for the potential splicing factor TLS". J. Biol. Chem. 276 (9): 6807–16. doi:10.1074/jbc.M008304200. PMID 11098054. 
  19. ^ Fujii R, Takumi T (December 2005). "TLS facilitates transport of mRNA encoding an actin-stabilizing protein to dendritic spines". J. Cell. Sci. 118 (Pt 24): 5755–65. doi:10.1242/jcs.02692. PMID 16317045. 
  20. ^ Takahama K, Kino K, Arai S, Kurokawa R, Oyoshi T (2008). "Identification of RNA binding specificity for the TET-family proteins". Nucleic Acids Symp Ser (Oxf) (52): 213–4. doi:10.1093/nass/nrn108. PMID 18776329. 
  21. ^ Law WJ, Cann KL, Hicks GG (March 2006). "TLS, EWS and TAF15: a model for transcriptional integration of gene expression". Brief Funct Genomic Proteomic 5 (1): 8–14. doi:10.1093/bfgp/ell015. PMID 16769671. 
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  24. ^ a b Uranishi H, Tetsuka T, Yamashita M, Asamitsu K, Shimizu M, Itoh M, Okamoto T (April 2001). "Involvement of the pro-oncoprotein TLS (translocated in liposarcoma) in nuclear factor-kappa B p65-mediated transcription as a coactivator". J. Biol. Chem. 276 (16): 13395–401. doi:10.1074/jbc.M011176200. PMID 11278855. 
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Further reading[edit]