SR protein-mediated inhibition of CFTR exon 9 inclusion: molecular characterization of the intronic splicing silencer.
SR protein-mediated inhibition of CFTR exon 9 inclusion: molecular characterization of the intronic splicing silencer.
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DOI：
10.1093/nar/gkm444
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发表时间：
2007
影响因子：
14.9
通讯作者：
Baralle FE
中科院分区：
文献类型：
--
作者：
Buratti E;Stuani C;De Prato G;Baralle FE
CFTR外显子9的内含子剪接沉默子（ISS）促进该外显子从成熟mRNA中排除。这种负面影响对于人类病理事件具有重要的后果，因为外显子9的缺乏与CF疾病的单症状和完全形式的发生密切相关。我们以前已经表明，ISS元素与SR蛋白家族的成员相互作用。在这项工作中，我们现在提供了SF 2/ASF和SRp 40作为与该元件结合的特异性SR蛋白的鉴定，并绘制了它们在IVS 9中的精确结合位点。我们还进行了ISS元素的功能分析，使用各种不相关的SR结合序列和不同的剪接系统。我们的研究结果表明，SR蛋白介导CFTR外显子9排除提供了一个'诱饵'序列在其次优供体位点附近。本研究的结果提供了一个深入了解内含子的“外显子”的机制，并提供了有用的迹象，旨在恢复外显子包含的新的治疗策略的发展。
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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