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dc.contributor.authorSingh, Natalia N.
dc.contributor.authorSingh, Ravindra N.
dc.contributor.authorAndrophy, Elliot J.
dc.date2022-08-11T08:09:35.000
dc.date.accessioned2022-08-23T16:36:44Z
dc.date.available2022-08-23T16:36:44Z
dc.date.issued2006-12-16
dc.date.submitted2009-04-02
dc.identifier.citationNucleic Acids Res. 2007;35(2):371-89. Epub 2006 Dec 14. <a href="http://dx.doi.org/10.1093/nar/gkl1050">Link to article on publisher's site</a>
dc.identifier.issn1362-4962 (Electronic)
dc.identifier.doi10.1093/nar/gkl1050
dc.identifier.pmid17170000
dc.identifier.urihttp://hdl.handle.net/20.500.14038/38854
dc.description.abstractHumans 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=17170000&dopt=Abstract">Link to Article in PubMed</a>
dc.subject*Alternative Splicing
dc.subjectBase Sequence
dc.subjectCell Line, Tumor
dc.subjectCyclic AMP Response Element-Binding Protein
dc.subject*Exons
dc.subjectHumans
dc.subjectMolecular Sequence Data
dc.subjectMutagenesis, Site-Directed
dc.subjectNerve Tissue Proteins
dc.subjectNucleic Acid Conformation
dc.subjectRNA
dc.subjectRNA Splice Sites
dc.subjectRNA Stability
dc.subjectRNA-Binding Proteins
dc.subject*Regulatory Sequences, Ribonucleic Acid
dc.subjectRibonucleases
dc.subjectRibonucleoprotein, U1 Small Nuclear
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleModulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes
dc.typeJournal Article
dc.source.journaltitleNucleic acids research
dc.source.volume35
dc.source.issue2
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2692&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/1693
dc.identifier.contextkey808455
refterms.dateFOA2022-08-23T16:36:44Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathoapubs/1693
dc.contributor.departmentDepartment of Medicine
dc.source.pages371-89


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