Hidden RNA pairings counteract the "first-come, first-served" splicing principle to drive stochastic choice in Dscam1 splice variants.
Hidden RNA pairings counteract the "first-come, first-served" splicing principle to drive stochastic choice in Dscam1 splice variants.
复制标题
隐藏的 RNA 配对抵消了“先来先服务”的剪接原则，从而驱动 Dscam1 剪接变体中的随机选择
DOI：
10.1126/sciadv.abm1763
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发表时间：
2022-01-28
期刊：
影响因子：
13.6
通讯作者：
Jin Y
中科院分区：
文献类型：
--
作者：
Dong H;Xu B;Guo P;Zhang J;Yang X;Li L;Fu Y;Shi J;Zhang S;Zhu Y;Shi Y;Zhou F;Bian L;You W;Shi F;Yang X;Huang J;He H;Jin Y
果蝇Dscam 1通过互斥剪接编码38，016种异构体;然而，这背后的调控机制尚未完全了解。在这里，我们发现了一组隐藏的RNA二级结构，平衡Dscam 1剪接变体的随机选择（指定的平衡器RNA二级结构）。体内突变分析揭示了这些平衡器相互作用的双重功能，在驱动随机选择的剪接变体，通过增强的包含远端外显子6的合作与对接位点选择器配对，形成一个更强的多域前体mRNA结构，并通过同时抑制包含近端外显子6的拮抗其对接位点选择器配对。因此，我们提供了一个优雅的分子模型的基础上的两套对接位点选择器和平衡器配对，这抵消了“先到先得”的原则之间的竞争和合作。我们的研究结果提供了概念和机制的动态和功能的远程RNA二级结构的见解。Balancer RNA二级结构驱动果蝇Dscam 1中外显子6剪接变体的随机选择
Drosophila melanogaster Dscam1 encodes 38,016 isoforms via mutually exclusive splicing; however, the regulatory mechanism behind this is not fully understood. Here, we found a set of hidden RNA secondary structures that balance the stochastic choice of Dscam1 splice variants (designated balancer RNA secondary structures). In vivo mutational analyses revealed the dual function of these balancer interactions in driving the stochastic choice of splice variants, through enhancement of the inclusion of distal exon 6s by cooperating with docking site–selector pairing to form a stronger multidomain pre-mRNA structure and through simultaneous repression of the inclusion of proximal exon 6s by antagonizing their docking site–selector pairings. Thus, we provide an elegant molecular model based on competition and cooperation between two sets of docking site–selector and balancer pairings, which counteracts the “first-come, first-served” principle. Our findings provide conceptual and mechanistic insight into the dynamics and functions of long-range RNA secondary structures. Balancer RNA secondary structures drive the stochastic choice of exon 6 splice variants in fly Dscam1.
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