CELF proteins regulate CFTR pre-mRNA splicing: essential role of the divergent domain of ETR-3.
CELF proteins regulate CFTR pre-mRNA splicing: essential role of the divergent domain of ETR-3.
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DOI：
10.1093/nar/gkq573
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发表时间：
2010-11
影响因子：
14.9
通讯作者：
Corcos L
中科院分区：
文献类型：
--
作者：
Dujardin G;Buratti E;Charlet-Berguerand N;Martins de Araujo M;Mbopda A;Le Jossic-Corcos C;Pagani F;Ferec C;Corcos L
囊性纤维化是一种由囊性纤维化跨膜传导调节因子（CFTR）基因突变引起的重要遗传性疾病。在许多导致疾病的改变中，前体mRNA剪接缺陷可以阻碍强制性外显子包含。CFTR外显子9剪接部分取决于内含子8末端的多态性UG（m）U（n）序列，其可以被TDP-43结合，导致部分外显子9跳跃。CELF蛋白，如CUG-BP 1和ETR-3，也可以结合UG重复序列并调节剪接。我们在这里表明，ETR-3，而不是CUG-BP 1，强烈刺激外显子9跳跃，虽然这两种蛋白质有效地结合到相同的RNA基序TDP-43和更高的亲和力。我们进一步表明，该外显子的跳跃可能是由于U2 AF 65和ETR-3分别结合到多态性U或UG延伸之间的功能拮抗作用。重要的是，我们证明了ETR-3的趋异结构域对于CFTR外显子9跳跃是至关重要的，如缺失和结构域交换实验所示。我们提出了一个模型，其中几个RNA结合事件占CFTR外显子9包含的复杂调控，与ETR-3和CUG-BP 1的显著不同的活动，其不同结构域的结构有关。
Cystic fibrosis is a prominent genetic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Among the many disease-causing alterations are pre-mRNA splicing defects that can hamper mandatory exon inclusion. CFTR exon 9 splicing depends in part on a polymorphic UG(m)U(n) sequence at the end of intron 8, which can be bound by TDP-43, leading to partial exon 9 skipping. CELF proteins, like CUG-BP1 and ETR-3, can also bind UG repeats and regulate splicing. We show here that ETR-3, but not CUG-BP1, strongly stimulates exon 9 skipping, although both proteins bind efficiently to the same RNA motif as TDP-43 and with higher affinity. We further show that the skipping of this exon may be due to the functional antagonism between U2AF65 and ETR-3 binding onto the polymorphic U or UG stretch, respectively. Importantly, we demonstrate that the divergent domain of ETR-3 is critical for CFTR exon 9 skipping, as shown by deletion and domain-swapping experiments. We propose a model whereby several RNA-binding events account for the complex regulation of CFTR exon 9 inclusion, with strikingly distinct activities of ETR-3 and CUG-BP1, related to the structure of their divergent domain.
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影响因子：
14.9
作者：
Goo YH;Cooper TA
通讯作者：
Cooper TA
影响因子：
4.5
作者：
Divangahi M;Balghi H;Danialou G;Comtois AS;Demoule A;Ernest S;Haston C;Robert R;Hanrahan JW;Radzioch D;Petrof BJ
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Petrof BJ
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30.8
作者：
CHU, CS;TRAPNELL, BC;CRYSTAL, RG
通讯作者：
CRYSTAL, RG
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4
作者：
Ladd, AN;Cooper, TA
通讯作者：
Cooper, TA
影响因子：
4
作者：
De Braekeleer, Marc;Ferec, Claude
通讯作者：
Ferec, Claude