Identification of SRSF10 as a regulator of SMN2 ISS-N1

Frederiksen, Sabrina B, Holm, Lise L, Larsen, Martin R, Doktor, Thomas K, Andersen, Henriette S, Hastings, Michelle L, Hua, Yimin, Krainer, Adrian R, Andresen, Brage S (March 2021) Identification of SRSF10 as a regulator of SMN2 ISS-N1. Human Mutation, 42 (3). pp. 246-260. ISSN 1059-7794

URL: https://www.ncbi.nlm.nih.gov/pubmed/33300159

DOI: 10.1002/humu.24149

Abstract

Understanding the splicing code can be challenging as several splicing factors bind to many splicing-regulatory elements. The SMN1 and SMN2 silencer element ISS-N1 is the target of the antisense oligonucleotide drug, Spinraza, which is the treatment against spinal muscular atrophy. However, limited knowledge about the nature of the splicing factors that bind to ISS-N1 and inhibit splicing exists. It is likely that the effect of Spinraza comes from blocking binding of these factors, but so far, an unbiased characterization has not been performed and only members of the hnRNP A1/A2 family have been identified by Western blot analysis and nuclear magnetic resonance to bind to this silencer. Employing an MS/MS-based approach and surface plasmon resonance imaging, we show for the first time that splicing factor SRSF10 binds to ISS-N1. Furthermore, using splice-switching oligonucleotides we modulated the splicing of the SRSF10 isoforms generating either the long or the short protein isoform of SRSF10 to regulate endogenous SMN2 exon 7 inclusion. We demonstrate that the isoforms of SRSF10 regulate SMN1 and SMN2 splicing with different strength correlating with the length of their RS domain. Our results suggest that the ratio between the SRSF10 isoforms is important for splicing regulation.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > congenital hereditary genetic diseases bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell cycle organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > oligonucleotide organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types diseases & disorders > congenital hereditary genetic diseases > spinal muscular atrophy bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > splicing factor
CSHL Authors:	Hua, Yimin Krainer, Adrian R.
Communities:	CSHL labs > Krainer lab CSHL Cancer Center Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	March 2021
Date Deposited:	06 May 2021 15:55
Last Modified:	13 Feb 2024 16:51
PMCID:	PMC7878440
URI:	https://repository.cshl.edu/id/eprint/40009

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