Correction of disease-associated exon skipping by synthetic exon-specific activators

Cartegni, L., Krainer, A. R. (2003) Correction of disease-associated exon skipping by synthetic exon-specific activators. Nature Structural Biology, 10 (2). pp. 120-125. ISSN 1072-8368

URL: http://www.ncbi.nlm.nih.gov/pubmed/12524529
DOI: 10.1038/nsb887

Abstract

Differential exon use is a hallmark of alternative splicing, a prevalent mechanism for generating protein isoform diversity. Many disease-associated mutations also affect pre-mRNA splicing, usually causing inappropriate exon skipping. SR proteins are essential splicing factors that recognize exonic splicing enhancers and drive exon inclusion. To emulate this function of SR proteins, we designed small chimeric effectors comprising a minimal synthetic RS domain covalently linked to an antisense moiety that targets an exon by Watson-Crick base pairing. Here we show that such synthetic effectors can mimic the functions of SR proteins and specifically restore wild type splicing when directed to defective BRCA1 or SMN2 pre-mRNA transcripts. This general approach can be used as a tool to investigate splicing mechanisms and modulate alternative splicing of specific genes, and as a therapeutic strategy to correct splicing defects responsible for numerous diseases.

Item Type: Paper
Uncontrolled Keywords: SPINAL MUSCULAR-ATROPHY MESSENGER-RNA ANTISENSE OLIGONUCLEOTIDES SINGLE NUCLEOTIDE NONSENSE MUTATION IN-VIVO GENE EXPRESSION SMN2 CONSEQUENCES
Subjects: diseases & disorders > congenital hereditary genetic diseases
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
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 > exons > exon skipping
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > RNA binding protein
CSHL Authors:
Communities: CSHL labs > Krainer lab
Depositing User: Matt Covey
Date Deposited: 01 Jul 2013 19:06
Last Modified: 01 Jul 2013 19:06
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27871

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