Mechanisms of translational control

项目总结 尽管蛋白质是生物学中最核心的过程之一，但许多关键问题仍然存在 核糖体的翻译是受调控的。翻译控制对人类健康至关重要，因为 众所周知，翻译的失调与无数的疾病有关，包括许多癌症。我们的 对基因表达的翻译控制的理解目前正在经历一种范式转换。直到 最近，人们认为所有的翻译控制都发生在核糖体决定启动或不启动的时候。 在起始密码子上。然而，最近的大量数据表明，翻译在启动后也受到广泛的监管 在随后的翻译“延长”阶段，发生了什么。因此，对翻译的规范 延伸是探索基因表达的翻译控制的一个不断扩大的前沿。 我的实验室使用了一系列强有力的动力和全基因组工具来研究 核糖体的伸长可以被调节来调节基因的表达。我们还直接与专家合作， 研究核糖体和信使核糖核酸结构。本提案侧重于使用这些方法进行调查 在分子水平上，核糖体进展缓慢与细胞健康和 生存能力，但分子机制尚不清楚。具体地说，我们的工作试图发现：1)新生的 多肽调节翻译的速度，2)核糖体的非规范运动如何改变基因 表达，3)信使核糖核酸修饰如何影响翻译效率，4)翻译后修饰 冲击翻译机器。这些研究将提供一个生化框架，以了解 控制核糖体伸长率有助于基因的全球表达。 总之，我们通过核糖体停滞来填补翻译调控这一新兴领域的关键空白。 机械装置。我们的研究将揭示通过翻译停滞进行的基因调控的广度，并剖析 翻译调控的分子机制(S)。总体而言，这项工作将挑战长期以来的范式，即 核糖体以基本一致的速率不分青红皂白地翻译大多数序列。从长远来看，我们的 这些发现可能是开发靶向疗法来治疗与脑血管病变相关的疾病的关键 平移伸长。

Project summary Despite being one of the most central processes in biology many key questions remain about how protein translation by the ribosome is regulated. Translational control is fundamentally important for human health as dysregulation of translation is known to be involved in myriad of diseases, including numerous cancers. Our understanding of the translational control of gene expression is currently undergoing a paradigm switch. Until recently it was thought that all translational control takes place when the ribosomes decide to, or not to, initiate on a start codon. However, a wealth of recent data suggests that translation is also widely regulated after initiation has occurred, during the subsequent `elongation' phase of translation. Thus, the regulation of translation elongation is an expanding frontier for exploring the translational control of gene expression. My lab uses a powerful compliment of kinetic and genome-wide tools to investigate how the speed of ribosome elongation can be modulated to regulate gene expression. We also directly collaborate with experts to investigate both ribosome and mRNA structures. This proposal focuses on using these approaches investigate situations at the molecular level where the slow progression of the ribosome has been linked to cell health and viability, but where molecular mechanisms are unknown. Specifically, our work seeks to discover: 1) how nascent peptides modulate the rate of translation, 2) how non-canonical movements of the ribosome change gene expression, 3) how mRNA modifications impact translation rates, and 4) how post-translational modifications impact the translation machinery. These studies will provide a biochemical framework for understanding how controlling ribosome elongation rates contributes globally to gene expression. In summary, we fill crucial gaps in the burgeoning field of translation regulation via ribosome stalling mechanisms. Our studies will reveal the breadth of gene regulation via translational stalling, and dissect the molecular mechanism(s) of translational control. Overall, this work will challenge the long-held paradigm that the ribosome indiscriminately translates the majority of sequences at a mostly uniform rate. In the long-term, our findings could be key for the development of targeted therapeutics to treat diseases linked to alterations of translation elongation.