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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Smith LD,Dickinson RL,Lucas CM,Cousins A,Malygin AA,Weldon C,Perrett AJ,Bottrill AR,Searle MS,Burley GA,Eperon ICdoi
10.1016/j.celrep.2014.08.051subject
Has Abstractpub_date
2014-10-09 00:00:00pages
193-205issue
1issn
2211-1247pii
S2211-1247(14)00727-Xjournal_volume
9pub_type
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