Regulation of mRNA fate

摘要 选择性剪接(AS)过程是一种强大的机制，可以从 蛋白质编码基因。来自同一基因的不同的信使核糖核酸异构体可以彼此微妙地不同，或者 它们的序列组成发生了根本性的变化。值得注意的是，人们对此知之甚少 这种不同的信使核糖核酸被转化为蛋白质。解决这个问题的一个有趣的线索来自我们的 最近的研究表明，选择性剪接的过程会影响基因的翻译效率 由此产生的信使核糖核酸亚型。在这个提议中，我们使用生化和分子方法来解开 错综复杂的机制耦合转录后基因表达。通过确定AS-TC元素如何调节- 我们将能够反驳或支持这一提议的中心假说，即交替-- 剪接的转录本被包装成功能不同的信使核糖核蛋白颗粒 (MRNPs)。如果与差异多聚核糖体结合相关的序列不直接控制翻译 启动或延长，然后我们将考虑我们的替代假设：很大一部分mRNA是- 形式多样性是由噪声剪接引起的，然后被一些未知的mrna排除在多聚核糖体之外。 监视路径。解决好这一重要问题，不仅可以揭示顺势因素对翻译的影响。 传统产量，但也将定义选择性剪接过程和mRNA之间的机械联系 翻译。从长远来看，我们的研究计划将为基于RNA的诊断提供新的机会 以及将适用于多种人类疾病的治疗方法。

Abstract The process of alternative splicing (AS) is a powerful mechanism for generating mRNA diversity from protein coding genes. Alternative mRNA isoforms from the same gene can differ subtly from each other or have radical alterations in their sequence composition. Remarkably, very little is known about whether or not this diverse pool of mRNA is converted to protein. One intriguing clue for solving this problem comes from our recent studies suggesting that the process of alternative splicing influences the translational efficiency of the resultant mRNA isoforms. In this proposal, we use both biochemical and molecular approaches to untangle the intricate mechanisms coupling post-transcriptional gene expression. By determining how AS-TC elements reg- ulate mRNA translation we will be able to refute or support the central hypothesis of this proposal, that alterna- tively spliced transcripts are packaged into functionally distinct messenger ribonucleoprotein particles (mRNPs). If sequences associated with differential polyribosome association do not directly control translation initiation or elongation, then we will consider our alternative hypothesis: that a significant fraction of mRNA iso- form diversity arises from noisy splicing which are then excluded from polyribosomes by some unknown mRNA surveillance pathway. Solving this important problem will not only reveal how cis-elements influence transla- tional yield, but will also define mechanistic links between the processes of alternative splicing and mRNA translation. In the long-term, our research program will facilitate new opportunities for RNA-based diagnostics and therapies that will be applicable to a wide array of human diseases.