Abstract
FUS (Fused-in-Sarcoma) is a multifunctional DNA/RNA binding protein linked to familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). Since FUS is localized mainly in the nucleus with nucleo-cytoplasmic shuttling, it is critical to understand physiological functions in the nucleus to clarify pathogenesis. Here we report a yeast two-hybrid screening identified FUS interaction with nuclear matrix-associated protein SAFB1 (scaffold attachment factor B1). FUS and SAFB1, abundant in chromatin-bound fraction, interact in a DNA-dependent manner. N-terminal SAP domain of SAFB1, a DNA-binding motif, was required for its localization to chromatin-bound fraction and splicing regulation. In addition, depletion of SAFB1 reduced FUS's localization to chromatin-bound fraction and splicing activity, suggesting SAFB1 could tether FUS to chromatin compartment thorough N-terminal DNA-binding motif. FUS and SAFB1 also interact with Androgen Receptor (AR) regulating ligand-dependent transcription. Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates. These findings indicate SAFB1 could be a FUS's functional platform in chromatin compartment to regulate RNA splicing and ligand-dependent transcription and shed light on the etiological significance of nuclear matrix-associated proteins in ALS pathogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alternative Splicing
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Amyotrophic Lateral Sclerosis / etiology
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Amyotrophic Lateral Sclerosis / genetics
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Amyotrophic Lateral Sclerosis / metabolism
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Animals
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Brain / metabolism
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Cell Line
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Chromatin / metabolism
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HEK293 Cells
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Humans
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Ligands
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Male
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Matrix Attachment Region Binding Proteins / chemistry
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Matrix Attachment Region Binding Proteins / genetics
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Matrix Attachment Region Binding Proteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mutant Proteins / chemistry
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Mutant Proteins / genetics
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Mutant Proteins / metabolism
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Nuclear Matrix / metabolism
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Nuclear Matrix-Associated Proteins / chemistry
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Nuclear Matrix-Associated Proteins / genetics
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Nuclear Matrix-Associated Proteins / metabolism*
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Protein Aggregation, Pathological / genetics
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Protein Aggregation, Pathological / metabolism
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Protein Interaction Domains and Motifs
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RNA-Binding Protein FUS / chemistry
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RNA-Binding Protein FUS / genetics
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RNA-Binding Protein FUS / metabolism*
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RNA-Binding Proteins / chemistry
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Receptors, Estrogen / chemistry
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Receptors, Estrogen / genetics
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Receptors, Estrogen / metabolism*
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Spinal Cord / metabolism
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Transcription, Genetic
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Two-Hybrid System Techniques
Substances
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Chromatin
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FUS protein, human
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Ligands
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MATR3 protein, human
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Matrix Attachment Region Binding Proteins
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Mutant Proteins
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Nuclear Matrix-Associated Proteins
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RNA-Binding Protein FUS
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RNA-Binding Proteins
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Receptors, Estrogen
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SAFB protein, human
Supplementary concepts
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Amyotrophic lateral sclerosis 1