Minor intron splicing is regulated by FUS and affected by ALS-associated FUS mutants

Reber, Stefan; Stettler, Jolanda; Filosa, G.; Colombo, Martino; Jutzi, D.; Lenzken, S. C.; Schweingruber, Christoph; Bruggmann, Rémy; Bachi, A.; Barabino, S. M.; Mühlemann, Oliver; Ruepp, Marc-David (2016). Minor intron splicing is regulated by FUS and affected by ALS-associated FUS mutants. EMBO journal, 35(11) Nature Publishing Group 10.15252/embj.201593791

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry
08 Faculty of Science > Department of Biology > Bioinformatics
08 Faculty of Science > Departement of Chemistry and Biochemistry > NCCR RNA & Disease

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Reber, Stefan; Stettler, Jolanda; Colombo, Martino; Schweingruber, Christoph; Bruggmann, Rémy; Mühlemann, Oliver and Ruepp, Marc-David

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

0261-4189

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Christina Schüpbach

Date Deposited:

13 Jul 2016 16:23

Last Modified:

13 Sep 2017 05:10

Publisher DOI:

10.15252/embj.201593791

BORIS DOI:

10.7892/boris.83479

URI:

https://boris.unibe.ch/id/eprint/83479

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