1. Minor intron splicing is regulated by <scp>FUS</scp> and affected by <scp>ALS</scp> ‐associated <scp>FUS</scp> mutants
- Author
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Daniel Jutzi, Angela Bachi, Giuseppe Filosa, Stefan Reber, Martino Colombo, Silvia M.L. Barabino, Marc-David Ruepp, Silvia C. Lenzken, Rémy Bruggmann, Jolanda Stettler, Oliver Mühlemann, Christoph Schweingruber, Reber, S, Stettler, J, Filosa, G, Colombo, M, Jutzi, D, Lenzken, S, Schweingruber, C, Bruggmann, R, Bachi, A, Barabino, S, Mühlemann, O, and Ruepp, M
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0301 basic medicine ,RNA Splicing ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,03 medical and health sciences ,Minor spliceosome ,540 Chemistry ,Transcriptional regulation ,Humans ,amyotrophic lateral sclerosi ,News & Views ,snRNP ,Molecular Biology ,Gene ,FUS ,General Immunology and Microbiology ,General Neuroscience ,Amyotrophic Lateral Sclerosis ,Intron ,RNA ,Molecular biology ,minor intron splicing ,Introns ,030104 developmental biology ,RNA splicing ,RNA-Binding Protein FUS ,570 Life sciences ,biology ,Mutant Proteins - Abstract
Fused in sarcoma (FUS) is a ubiquitously expressed RNA-binding protein proposed to function in various RNA metabolic pathways, including transcription regulation, pre-mRNA splicing, RNA transport and microRNA processing. Mutations in the FUS gene were identified in patients with amyotrophic lateral sclerosis (ALS), but the pathomechanisms by which these mutations cause ALS are not known. Here, we show that FUS interacts with the minor spliceosome constituent U11 snRNP, binds preferentially to minor introns and directly regulates their removal. Furthermore, a FUS knockout in neuroblastoma cells strongly disturbs the splicing of minor intron-containing mRNAs, among them mRNAs required for action potential transmission and for functional spinal motor units. Moreover, an ALS-associated FUS mutant that forms cytoplasmic aggregates inhibits splicing of minor introns by trapping U11 and U12 snRNAs in these aggregates. Collectively, our findings suggest a possible pathomechanism for ALS in which mutated FUS inhibits correct splicing of minor introns in mRNAs encoding proteins required for motor neuron survival.
- Published
- 2016
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