SANS (USH1G) Regulates Pre-mRNA Splicing by Mediating the Intra-nuclear Transfer of Tri-snRNP Complexes

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2021 May 23

PMID 34023904

Citations 12

Authors

Adem Yildirim

Sina Mozaffari-Jovin

Ann-Kathrin Wallisch

Jessica Schafer

Sebastian E J Ludwig

Henning Urlaub

Reinhard Luhrmann

Uwe Wolfrum

Affiliations

Soon will be listed here.

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.

Citing Articles

Identification of Unexpected Pathomechanisms Underlying the Human Usher Syndrome.

Wolfrum U, Linnert J, Guler B, Klein J, Fritze J, Wenck N Adv Exp Med Biol. 2025; 1468:171-175.

PMID: 39930191 DOI: 10.1007/978-3-031-76550-6_28.

Nuclear-Cytoplasmic Shuttling of the Usher Syndrome 1G Protein SANS Differs from Its Paralog ANKS4B.

Fritze J, Stiehler F, Wolfrum U Cells. 2024; 13(22).

PMID: 39594604 PMC: 11592671. DOI: 10.3390/cells13221855.

Pathogenic Variants in /SANS Alter Protein Interaction with Pre-RNA Processing Factors PRPF6 and PRPF31 of the Spliceosome.

Fritze J, Stiehler F, Wolfrum U Int J Mol Sci. 2023; 24(24).

PMID: 38139438 PMC: 10744108. DOI: 10.3390/ijms242417608.

Alternative splicing in shaping the molecular landscape of the cochlea.

Kim K, Koo H, Bok J Front Cell Dev Biol. 2023; 11:1143428.

PMID: 36936679 PMC: 10018040. DOI: 10.3389/fcell.2023.1143428.

The Usher syndrome 1C protein harmonin regulates canonical Wnt signaling.

Schafer J, Wenck N, Janik K, Linnert J, Stingl K, Kohl S Front Cell Dev Biol. 2023; 11:1130058.

PMID: 36846582 PMC: 9944737. DOI: 10.3389/fcell.2023.1130058.

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