SR protein-mediated inhibition of CFTR exon 9 inclusion: molecular characterization of the intronic splicing silencer

被引:43
作者
Buratti, Ernanuele
Stuani, Cristiana
De Prato, Greta
Baralle, Francisco E.
机构
[1] International Centre for Genetic Engineering and Biotechnology (ICGEB)
关键词
D O I
10.1093/nar/gkm444
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:4359 / 4368
页数:10
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