αCP binding to a cytosine-rich subset of polypyrimidine tracts drives a novel pathway of cassette exon splicing in the mammalian transcriptome.
αCP binding to a cytosine-rich subset of polypyrimidine tracts drives a novel pathway of cassette exon splicing in the mammalian transcriptome.
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αCP结合了多吡啶氨酸的富含胞嘧啶的子集，在哺乳动物转录组中驱动了盒式外显子剪接的新途径。
DOI：
10.1093/nar/gkw088
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发表时间：
2016-03-18
影响因子：
14.9
通讯作者：
Liebhaber SA
中科院分区：
文献类型：
--
作者：
Ji X;Park JW;Bahrami-Samani E;Lin L;Duncan-Lewis C;Pherribo G;Xing Y;Liebhaber SA
选择性剪接（AS）是哺乳动物转录组复杂性的强大生成器。剪接位点的特异性由转录本上的顺式作用决定簇与特异性RNA结合蛋白的相互作用控制。这些相互作用经常定位于内含子富含U的聚嘧啶段（PPT），其位于大多数剪接受体连接的5′端。α CP（也称为多聚C结合蛋白（PCBP）和hnRNPE）包含KH结构域蛋白的一个子集，对富含C的多聚嘧啶基序具有高亲和力和特异性。在这里，我们证明了α CP通过与位于α CP增强的外显子片段5′端的富含C的聚嘧啶片段子集结合，促进了一个定义的盒式外显子子集的剪接。这种剪接受体活性的增强与α CP与U2 snRNP复合物的相互作用有关，并且可能通过与典型聚嘧啶束结合蛋白U2AF 65的协同相互作用介导。α CP靶向外显子的分析预测对基本细胞功能的实质性影响。这些发现使我们得出结论，α CP在调节剪接活性和包含一系列盒式外显子中发挥直接和全局作用，从而驱动哺乳动物转录组内剪接位点调节的新途径。
Alternative splicing (AS) is a robust generator of mammalian transcriptome complexity. Splice site specification is controlled by interactions of cis-acting determinants on a transcript with specific RNA binding proteins. These interactions are frequently localized to the intronic U-rich polypyrimidine tracts (PPT) located 5′ to the majority of splice acceptor junctions. αCPs (also referred to as polyC-binding proteins (PCBPs) and hnRNPEs) comprise a subset of KH-domain proteins with high affinity and specificity for C-rich polypyrimidine motifs. Here, we demonstrate that αCPs promote the splicing of a defined subset of cassette exons via binding to a C-rich subset of polypyrimidine tracts located 5′ to the αCP-enhanced exonic segments. This enhancement of splice acceptor activity is linked to interactions of αCPs with the U2 snRNP complex and may be mediated by cooperative interactions with the canonical polypyrimidine tract binding protein, U2AF65. Analysis of αCP-targeted exons predicts a substantial impact on fundamental cell functions. These findings lead us to conclude that the αCPs play a direct and global role in modulating the splicing activity and inclusion of an array of cassette exons, thus driving a novel pathway of splice site regulation within the mammalian transcriptome.