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RNA-binding protein FUS
RNA-binding protein fused in sarcoma/translocated in liposarcoma (FUS/TLS), also known as heterogeneous nuclear ribonucleoprotein P2 is a protein that in humans is encoded by the FUS gene.
FUS/TLS was initially identified as a fusion protein (FUS-CHOP) produced as a result of chromosomal translocations in human cancers, especially liposarcomas. 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.
FUS/TLS was independently identified as the hnRNP P2 protein, a subunit of a complex involved in the maturation of pre-mRNA.
FUS/TLS is a member of the FET protein family that also includes the EWS protein, the TATA-binding protein TBP-associated factor TAFII68/TAF15, and the Drosophila cabeza/SARF protein.
FUS/TLS, EWS and 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 demethylated at arginine residues and a C-terminal zinc finger motif.
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.
Consistently, in vitro studies have shown that FUS/TLS binds RNA, single-stranded DNA and (with lower affinity) double-stranded DNA. 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. 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. FUS/TLS has also been proposed to bind human telomeric RNA (UUAGGG)4 and single-stranded human telomeric DNA in vitro.
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. Indeed, FUS/TLS interacts with several nuclear receptors. and with gene-specific transcription factors such as Spi-1/PU.1. or NF-κB. 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. Recently, FUS/TLS was also shown to repress the transcription of RNAP III genes and to co-immunoprecipitate with TBP and the TFIIIB complex.
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RNA-binding protein FUS
RNA-binding protein fused in sarcoma/translocated in liposarcoma (FUS/TLS), also known as heterogeneous nuclear ribonucleoprotein P2 is a protein that in humans is encoded by the FUS gene.
FUS/TLS was initially identified as a fusion protein (FUS-CHOP) produced as a result of chromosomal translocations in human cancers, especially liposarcomas. 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.
FUS/TLS was independently identified as the hnRNP P2 protein, a subunit of a complex involved in the maturation of pre-mRNA.
FUS/TLS is a member of the FET protein family that also includes the EWS protein, the TATA-binding protein TBP-associated factor TAFII68/TAF15, and the Drosophila cabeza/SARF protein.
FUS/TLS, EWS and 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 demethylated at arginine residues and a C-terminal zinc finger motif.
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.
Consistently, in vitro studies have shown that FUS/TLS binds RNA, single-stranded DNA and (with lower affinity) double-stranded DNA. 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. 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. FUS/TLS has also been proposed to bind human telomeric RNA (UUAGGG)4 and single-stranded human telomeric DNA in vitro.
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. Indeed, FUS/TLS interacts with several nuclear receptors. and with gene-specific transcription factors such as Spi-1/PU.1. or NF-κB. 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. Recently, FUS/TLS was also shown to repress the transcription of RNAP III genes and to co-immunoprecipitate with TBP and the TFIIIB complex.