Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes

Humans have two nearly identical copies of the survival motor neuron (SMN ) gene, SMN1 and SMN2. Homozygous loss of SMN1 causes spinal muscular atrophy (SMA). SMN2 is unable to prevent the disease due to skipping of exon 7. Using a systematic approach of in vivo selection, we have previously demonst...

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Main Authors:	Singh, Natalia N., Singh, Ravindra N., Androphy, Elliot J.
Format:	Online
Language:	English
Published:	Oxford University Press 2007
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1802598/

id	pubmed-1802598
recordtype	oai_dc
spelling	pubmed-18025982007-03-01 Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes Singh, Natalia N. Singh, Ravindra N. Androphy, Elliot J. Structural Biology Humans have two nearly identical copies of the survival motor neuron (SMN ) gene, SMN1 and SMN2. Homozygous loss of SMN1 causes spinal muscular atrophy (SMA). SMN2 is unable to prevent the disease due to skipping of exon 7. Using a systematic approach of in vivo selection, we have previously demonstrated that a weak 5′ splice site (ss) serves as the major cause of skipping of SMN2 exon 7. Here we show the inhibitory impact of RNA structure on the weak 5′ ss of exon 7. We call this structure terminal stem–loop 2 (TSL2). Confirming the inhibitory nature of TSL2, point mutations that destabilize TSL2 promote exon 7 inclusion in SMN2, whereas strengthening of TSL2 promotes exon 7 skipping even in SMN1. We also demonstrate that TSL2 negatively affects the recruitment of U1snRNP at the 5′ ss of exon 7. Using enzymatic structure probing, we confirm that the sequence at the junction of exon 7/intron 7 folds into TSL2 and show that mutations in TSL2 cause predicted structural changes in this region. Our findings reveal for the first time the critical role of RNA structure in regulation of alternative splicing of human SMN. Oxford University Press 2007-01 2006-12-14 /pmc/articles/PMC1802598/ /pubmed/17170000 http://dx.doi.org/10.1093/nar/gkl1050 Text en © 2006 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Singh, Natalia N. Singh, Ravindra N. Androphy, Elliot J.
spellingShingle	Singh, Natalia N. Singh, Ravindra N. Androphy, Elliot J. Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes
author_facet	Singh, Natalia N. Singh, Ravindra N. Androphy, Elliot J.
author_sort	Singh, Natalia N.
title	Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes
title_short	Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes
title_full	Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes
title_fullStr	Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes
title_full_unstemmed	Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes
title_sort	modulating role of rna structure in alternative splicing of a critical exon in the spinal muscular atrophy genes
description	Humans have two nearly identical copies of the survival motor neuron (SMN ) gene, SMN1 and SMN2. Homozygous loss of SMN1 causes spinal muscular atrophy (SMA). SMN2 is unable to prevent the disease due to skipping of exon 7. Using a systematic approach of in vivo selection, we have previously demonstrated that a weak 5′ splice site (ss) serves as the major cause of skipping of SMN2 exon 7. Here we show the inhibitory impact of RNA structure on the weak 5′ ss of exon 7. We call this structure terminal stem–loop 2 (TSL2). Confirming the inhibitory nature of TSL2, point mutations that destabilize TSL2 promote exon 7 inclusion in SMN2, whereas strengthening of TSL2 promotes exon 7 skipping even in SMN1. We also demonstrate that TSL2 negatively affects the recruitment of U1snRNP at the 5′ ss of exon 7. Using enzymatic structure probing, we confirm that the sequence at the junction of exon 7/intron 7 folds into TSL2 and show that mutations in TSL2 cause predicted structural changes in this region. Our findings reveal for the first time the critical role of RNA structure in regulation of alternative splicing of human SMN.
publisher	Oxford University Press
publishDate	2007
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1802598/
_version_	1611394451978059776

Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes

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