RNA-binding protein fused in sarcoma/translocated in liposarcoma (FUS/TLS), also known asheterogeneous nuclear ribonucleoprotein P2 is aprotein that in humans is encoded by theFUSgene.[5][6][7][8][9][10]
FUS/TLS was initially identified as afusion protein (FUS-CHOP) produced as a result of chromosomal translocations in human cancers, especiallyliposarcomas.[6][9] 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 (e.g.CHOP) conferring a strong transcriptional activation domain onto the fusion proteins.[11][12]
FUS/TLS was independently identified as the hnRNP P2 protein, a subunit of a complex involved in the maturation ofpre-mRNA.[13]
TheN-terminal end of FUS appears to be involved in transcriptional activation, while theC-terminal end is involved in protein and RNA binding. In addition recognition sites for the transcription factorsAP2,GCF,Sp1 have been identified in FUS.[17]
Consistently, in vitro studies have shown that FUS/TLS binds RNA, single-stranded DNA and (with lower affinity) double-stranded DNA.[7][9][18][19][20][21] 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.[22] 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.[23] FUS/TLS has also been proposed to bind human telomeric RNA (UUAGGG)4 and single-stranded human telomeric DNA in vitro.[24]
Beyondnucleic acid binding, FUS/TLS was also found to associate with both general and more specialized protein factors to influence the initiation of transcription.[25] Indeed, FUS/TLS interacts with severalnuclear receptors.[26] and with gene-specific transcription factors such as Spi-1/PU.1.[27] orNF-κB.[28] 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.[29][30][31] Recently, FUS/TLS was also shown to repress the transcription of RNAP III genes and to co-immunoprecipitate with TBP and the TFIIIB complex.[32]
FUS appears at sites ofDNA damage very rapidly, which suggests that FUS is orchestrating theDNA repair response.[33] The function of FUS in the DNA damage response inneurons involves a direct interaction withhistone deacetylase 1 (HDAC1). The recruitment of FUS to double-strand break sites is important for DNA damage response signaling and for repair of DNA damage.[33] FUS loss-of-function results in increased DNA damage in neurons. Mutations in the FUSnuclear localization sequence impairs thepoly (ADP-ribose) polymerase (PARP)-dependent DNA damage response.[34] This impairment leads to neurodegeneration and FUS aggregate formation. Such FUS aggregates are a pathological hallmark of theneurodegenerative diseaseamyotrophic lateral sclerosis (ALS).
In 2009 two separate research groups analysed 26 unrelated families who presented with a type6ALS phenotype, and found 14 mutations in theFUS gene.[36][37]
The toxic mechanism by which mutant FUS causes ALS is currently unclear. It is known that many of the ALS-linked mutations are located in its C-terminal nuclear localisation signal, resulting in it being located in thecytoplasm rather than the nucleus (where wild-type FUS primarily resides).[42] This suggests either a loss of nuclear function, or a toxic gain of cytoplasmic function, is responsible for the development of this type of ALS. Many researchers believe the toxic gain of cytoplasmic function model to be more likely as mouse models that do not express FUS, and therefore have a complete loss of nuclear FUS function, do not develop clear ALS-like symptoms.[43]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Eneroth M, Mandahl N, Heim S, Willén 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.PMID2372777.
^abRabbitts 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.PMID7503811.S2CID5964293.
^abcPrasad 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.PMID7970732.
^abMorohoshi 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.PMID9795213.
^Rappsilber J, Friesen WJ, Paushkin S, Dreyfuss G, Mann M (July 2003). "Detection of arginine dimethylated peptides by parallel precursor ion scanning mass spectrometry in positive ion mode".Anal. Chem.75 (13):3107–14.doi:10.1021/ac026283q.PMID12964758.
^Zinszner H, Sok J, Immanuel D, Yin Y, Ron D (August 1997). "TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling".J. Cell Sci.110 (15):1741–50.doi:10.1242/jcs.110.15.1741.PMID9264461.
^Kwiatkowski TJ, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH (February 2009). "Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis".Science.323 (5918):1205–1208.Bibcode:2009Sci...323.1205K.doi:10.1126/science.1166066.PMID19251627.S2CID12774563.
^Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE (September 2005). "A human protein-protein interaction network: a resource for annotating the proteome".Cell.122 (6):957–68.doi:10.1016/j.cell.2005.08.029.hdl:11858/00-001M-0000-0010-8592-0.PMID16169070.S2CID8235923.
Panagopoulos I, Mandahl N, Ron D, Höglund M, Nilbert M, Mertens F, Mitelman F, Aman P (1995). "Characterization of the CHOP breakpoints and fusion transcripts in myxoid liposarcomas with the 12;16 translocation".Cancer Res.54 (24):6500–3.PMID7987849.
Ichikawa H, Shimizu K, Hayashi Y, Ohki M (1994). "An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation".Cancer Res.54 (11):2865–8.PMID8187069.
Zinszner H, Sok J, Immanuel D, Yin Y, Ron D (1997). "TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling".J. Cell Sci.110 (15):1741–50.doi:10.1242/jcs.110.15.1741.PMID9264461.
