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2011年1月9日，《自然·结构和分子生物学》（Nature Structural & Molecular Biology） 在线发表了浙江大学生命科学学院金勇丰课题组原创性研究成果：应用RNA物理竞争原理，数学模型结合分子生物学方法破解了RNA互斥剪接的调控机制，并阐 明了最复杂的Dscam等基因的可变剪接的调控机制，该机制可能普遍适用于不同生物和基因。以前人们大多认为mRNA以线型的形式出现，该发现展示了美丽 的mRNA结构动态及其新调控功能。被审稿专家认为“The experiments provide the clearest evidence to date for the formation and function of long range secondary structures”。上述工作完全由金勇丰课题组在国内实验室完成。 可变剪接是产生蛋白质和功能的多样性的重要途径，对细胞分化和发育以及疾病发生等至关重要。人类高达95%以上的基因是可变剪接的。这种可变剪接产 生的产物数目是极其惊人的，如果蝇Dscam(唐氏综合症细胞黏附分子)基因通过互斥剪接可产生的异构体多达38 016种，是其整个基因组基因数目的两倍。但是，对其产生机制并不清楚。由于Dscam等基因与神经和免疫功能等相关，该研究成果不仅对深入认识基因表达的调控机制，而且对阐析疾病发生发展机制具有十分重要的意义。（生物谷Bioon.com） 生物谷推荐原文出处： Nature Structural & Molecular Biology doi:10.1038/nsmb.1959 RNA secondary structure in mutually exclusive splicing Yun Yang,1, 3 Leilei Zhan,1, 3 Wenjing Zhang,1, 3 Feng Sun,1 Wenfeng Wang,1 Nan Tian,1 Jingpei Bi,1 Haitao Wang,1 Dike Shi,1 Yajian Jiang,1 Yaozhou Zhang2 & Yongfeng Jin1 Mutually exclusive splicing is a regulated means to generate protein diversity, but the underlying mechanisms are poorly understood. Here comparative genome analysis revealed the built-in intronic elements for controlling mutually exclusive splicing of the 14-3-3ξ pre-mRNA. These elements are clade specific but are evolutionarily conserved at the secondary structure level. Combined evidence revealed the triple functions of these inter-intronic RNA pairings in synergistically ensuring the selection of only one of multiple exons, through activation of the proximal variable exon outside the loop by the approximation of cis elements, and simultaneous repression of the exon within the loop, in combination with the physical competition of RNA pairing. Additionally, under this model, we also deciphered a similar structural code in exon clusters 4 and 9 of Dscam (38,016 isoforms) and Mhc (480 isoforms). Our findings suggest a broadly applicable mechanism to ensure mutually exclusive splicing. |
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