SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes

6533b870fe1ef96bd12d070a

RESEARCH PRODUCT

SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes

Sina Mozaffari-jovin Sina Mozaffari-jovin Reinhard Lührmann Adem Yildirim Uwe Wolfrum Henning Urlaub Ann-kathrin Wallisch Jessica Ries Sebastian E. J. Ludwig

subject

Proteomics AcademicSubjects/SCI00010 Ribonucleoprotein U4-U6 Small Nuclear SF3B1 Gene Mass Spectrometry 0302 clinical medicine RNA Small Nuclear RNA Precursors In Situ Hybridization Fluorescence Ribonucleoprotein 0303 health sciences Chemistry Ribonucleoproteins Small Nuclear Immunohistochemistry Cell biology DNA-Binding Proteins medicine.anatomical_structure Gene Knockdown Techniques RNA splicing RNA Splicing Factors Usher Syndromes Spliceosome Coiled Bodies Nerve Tissue Proteins Biology Minor Histocompatibility Antigens 03 medical and health sciences Microscopy Electron Transmission RNA and RNA-protein complexes Genetics medicine Humans snRNP Eye Proteins Gene Cell Proliferation 030304 developmental biology Cell Nucleus RNA medicine.disease Phosphoproteins Ciliopathy Alternative Splicing Cell nucleus HEK293 Cells Cajal body Cytoplasm Spliceosomes Nucleus 030217 neurology & neurosurgery Transcription Factors

description

Abstract Splicing is catalyzed by the spliceosome, a compositionally dynamic complex assembled stepwise on pre-mRNA. We reveal links between splicing machinery components and the intrinsically disordered ciliopathy protein SANS. Pathogenic mutations in SANS/USH1G lead to Usher syndrome—the most common cause of deaf-blindness. Previously, SANS was shown to function only in the cytosol and primary cilia. Here, we have uncovered molecular links between SANS and pre-mRNA splicing catalyzed by the spliceosome in the nucleus. We show that SANS is found in Cajal bodies and nuclear speckles, where it interacts with components of spliceosomal sub-complexes such as SF3B1 and the large splicing cofactor SON but also with PRPFs and snRNAs related to the tri-snRNP complex. SANS is required for the transfer of tri-snRNPs between Cajal bodies and nuclear speckles for spliceosome assembly and may also participate in snRNP recycling back to Cajal bodies. SANS depletion alters the kinetics of spliceosome assembly, leading to accumulation of complex A. SANS deficiency and USH1G pathogenic mutations affects splicing of genes related to cell proliferation and human Usher syndrome. Thus, we provide the first evidence that splicing dysregulation may participate in the pathophysiology of Usher syndrome.

year	journal	country	edition	language
2021-05-22	Nucleic Acids Research

https://doi.org/10.1093/nar/gkab386