RNA-binding protein FUS

RNA-binding protein FUS/TLS (FUsed in Sarcoma/Translocated in LipoSarcoma), also known as heterogeneous nuclear ribonucleoprotein P2 is a protein that in humans is encoded by the FUS gene.^{[3][4][5][6][7][8]}

Discovery

FUS/TLS was initially identified as a

Consistently, in vitro studies have shown that FUS/TLS binds RNA, single-stranded DNA and (with lower affinity) double-stranded DNA.[5]^{[7][16][17][18][19]} 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.^[20] 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.^[21] FUS/TLS has also been proposed to bind human telomeric RNA (UUAGGG)4 and single-stranded human telomeric DNA in vitro.^[22]

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.^[23] Indeed, FUS/TLS interacts with several nuclear receptors.^[24] and with gene-specific transcription factors such as Spi-1/PU.1.^[25] or NF-κB.^[26] 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.^[27][28][29] Recently, FUS/TLS was also shown to repress the transcription of RNAP III genes and to co-immunoprecipitate with TBP and the TFIIIB complex.^[30]

FUS-mediated DNA repair

FUS appears at sites of

Clinical significance

FUS gene rearrangement has been implicated in the pathogenesis of myxoid liposarcoma, low-grade fibromyxoid sarcoma, Ewing sarcoma, and a wide range of other malignant and benign tumors (see FET protein family).^[33]

In 2009 two separate research groups analysed 26 unrelated families who presented with a type6

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 the cytoplasm rather than the nucleus (where wild-type FUS primarily resides).[40] 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.^[41]

Interactions

FUS has been shown to

• FUSIP1/SRSF10^[29]
• HDAC1^[31]
• ILF3,^[42]
• PRMT1,^[43][44][45]
• RELA,^[26]
• RNA polymerase II (C-terminal domain)^[46]
• SPI1,^[25] and
• TNPO1.^[47][48]

References