Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/29298
Title: A Targeted Oligonucleotide Enhancer of SMN2 Exon 7 Splicing Forms Competing Quadruplex and Protein Complexes in Functional Conditions
Authors: Smith, Lindsay D.
Dickinson, Rachel L.
Lucas, Christian M.
Cousins, Alex
Malygin, Alexey A.
Weldon, Carika
Perrett, Andrew J.
Bottrill, Andrew R.
Searle, Mark S.
Burley, Glenn A.
Eperon, Ian C.
First Published: 25-Sep-2014
Publisher: Elsevier
Citation: Cell Reports, 2014, 9 (1), pp. 193-205
Abstract: The use of oligonucleotides to activate the splicing of selected exons is limited by a poor understanding of the mechanisms affected. A targeted bifunctional oligonucleotide enhancer of splicing (TOES) anneals to SMN2 exon 7 and carries an exonic splicing enhancer (ESE) sequence. We show that it stimulates splicing specifically of intron 6 in the presence of repressing sequences in intron 7. Complementarity to the 5' end of exon 7 increases U2AF65 binding, but the ESE sequence is required for efficient recruitment of U2 snRNP. The ESE forms at least three coexisting discrete states: a quadruplex, a complex containing only hnRNP F/H, and a complex enriched in the activator SRSF1. Neither hnRNP H nor quadruplex formation contributes to ESE activity. The results suggest that splicing limited by weak signals can be rescued by rapid exchange of TOES oligonucleotides in various complexes and raise the possibility that SR proteins associate transiently with ESEs.
DOI Link: 10.1016/j.celrep.2014.08.051
eISSN: 2211-1247
Links: http://www.sciencedirect.com/science/article/pii/S221112471400727X
http://hdl.handle.net/2381/29298
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2014. This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Biochemistry

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