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

Yildirim, A., Mozaffari-Jovin, S., Wallisch, A. K., Schäfer, J., Ludwig, S. E. J., Urlaub, H., et al. (2021). SANS (USH1G) regulates pre-mRNA splicing by mediating the intra-nuclear transfer of tri-snRNP complexes. Nucleic Acids Research, 49(10), 5845-5866. doi:10.1093/nar/gkab386.

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Yildirim, A., Author
Mozaffari-Jovin, S.1, Author              
Wallisch, A. K., Author
Schäfer, J., Author
Ludwig, S. E. J.2, Author              
Urlaub, H.3, Author              
Lührmann, R.1, Author              
Wolfrum, U., Author
Affiliations:
1Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578576              
2Department of Cellular Biochemistry, MPI for Biophysical Chemistry, Max Planck Society, ou_578576              
3Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              

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 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.

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Language(s): eng - English
 Dates: 2021-05-222021-06-04
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1093/nar/gkab386
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Title: Nucleic Acids Research
Source Genre: Journal
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Pages: - Volume / Issue: 49 (10) Sequence Number: - Start / End Page: 5845 - 5866 Identifier: -