The International Journal of Biochemistry & Cell Biology
Molecules in focusFused in sarcoma/translocated in liposarcoma: A multifunctional DNA/RNA binding protein
Introduction
Mammalian gene expression comprises a series of integrated processes including transcription, RNA synthesis, mRNA processing, translation and post-translational processing of the protein. These processes are connected by a group of structurally similar DNA/RNA binding proteins. One of these proteins is the fused in sarcoma/translocated in liposarcoma (FUS/TLS), a member of the FUS/Ewing's sarcoma/TATA-binding protein-associated factor (FET) (formerly known as TET (TLS/E/T)) protein family. Originally identified in human myxoid liposarcomas in 1993, the FUS/TLS gene plays a critical role in the formation of fusion proteins related to a variety of cancers, including acute myeloid leukaemia and Ewing's tumor (Law et al., 2006). FUS/TLS serves multiple unique functions in RNA splicing, RNA transport and formation of fusion oncoproteins. Recently, several FUS/TLS mutations have been found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) patients, implicating a pathogenic role of this protein in neurodegenerative disease (Kwiatkowski et al., 2009, Vance et al., 2009, Lagier-Tourenne et al., 2010).
Section snippets
Structure
The FUS/TLS gene (approximately 12 kb) consists of 15 exons and 14 introns (Morohoshi et al., 1998). Its putative promoter has features of a housekeeping gene promoter, including an absence of TATA boxes (Aman et al., 1996). FUS/TLS was initially reported as a component of the fusion gene, TLS-CCAAT enhancer-binding homologous protein (CHOP), resulting from a chromosome translocation t(12;16)(q13.3;p11.2) seen in myxoid liposarcomas (Crozat et al., 1993). FUS/TLS also fuses to the
Expression, cellular location and regulation
The human FUS/TLS gene is constitutively activated and ubiquitously expressed in human tissues and cultured cell lines, including the heart, brain, placenta, lung, liver, kidney, pancreas, spleen, thymus and prostate, but is absent from cardiac endothelium, cardiac muscle cells and melanocytes (Aman et al., 1996, Andersson et al., 2008, Morohoshi et al., 1996). The expression level of FUS/TLS is heterogeneous among different tissues. The FUS/TLS gene is downregulated in differentiated human
FUS/TLS in DNA/RNA binding
The C-terminal RNA recognition motif (RRM), together with the flanking G-rich regions, is thought to be crucial for RNA binding (Burd and Dreyfuss, 1994). Initial studies suggested these motifs preferentially bind GGUG RNA motifs, both in vivo and in vitro (Crozat et al., 1993, Prasad et al., 1994, Zinszner et al., 1997). However, Zinszner et al. (1997) suggests that the RRM is not solely responsible for RNA targeting, as a truncated FUS/TLS protein lacking RRM still recognizes RNA. Indeed, the
Medical applications: link between FUS/TLS and neurodegenerative disease
ALS is a fatal neurodegenerative disease in which the loss of motor neurons causes progressive muscle wasting and paralysis. ALS shows some clinical, pathological and genetic overlap with FTLD, a disorder characterised by dementia caused by degeneration of the frontal and temporal lobes of the brain. ALS and FTLD are increasingly considered to be components of a disease spectrum (Lagier-Tourenne et al., 2010). To date, over 30 mutations in FUS/TLS gene have been described in approximately 4% of
Acknowledgements
National Health and Medical Research Council of Australia grants 570957 and 511941 to IPB and a University of Sydney Postgraduate Award to STW.
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