Nucleic Acids Research Advance Access originally published online on June 18, 2007
Nucleic Acids Research 2007 35(13):4359-4368; doi:10.1093/nar/gkm444
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Nucleic Acids Research, 2007, Vol. 35, No. 13 4359-4368
© 2007 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.
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SR protein-mediated inhibition of CFTR exon 9 inclusion: molecular characterization of the intronic splicing silencer
International Centre for Genetic Engineering and Biotechnology (ICGEB) 34012 Trieste, Italy
*To whom correspondence should be addressed. Tel: +0039 040 3757337; Fax: +0039 040 3757361; Email: baralle{at}icgeb.org
Received January 23, 2007. Revised May 14, 2007. Accepted May 18, 2007.
The intronic splicing silencer (ISS) of CFTR exon 9 promotes exclusion of this exon from the mature mRNA. This negative influence has important consequences with regards to human pathologic events, as lack of exon 9 correlates well with the occurrence of monosymptomatic and full forms of CF disease. We have previously shown that the ISS element interacts with members of the SR protein family. In this work, we now provide the identification of SF2/ASF and SRp40 as the specific SR proteins binding to this element and map their precise binding sites in IVS9. We have also performed a functional analysis of the ISS element using a variety of unrelated SR-binding sequences and different splicing systems. Our results suggest that SR proteins mediate CFTR exon 9 exclusion by providing a ‘decoy’ sequence in the vicinity of its suboptimal donor site. The results of this study give an insight on intron ‘exonization’ mechanisms and provide useful indications for the development of novel therapeutic strategies aimed at the recovery of exon inclusion.
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