Mechanisms of translational control

项目摘要 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是蛋白质是如何 核糖体的翻译受到调节。翻译控制对于人类健康至关重要， 已知翻译的失调与包括许多癌症在内的许多疾病有关。我们 对基因表达的翻译控制的理解目前正在经历范式转换。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时。 在起始密码子上然而，大量的最新数据表明，翻译在启蒙后也受到广泛的调节 在随后的翻译“延伸”阶段发生。因此，翻译的规则 延伸是探索基因表达的翻译控制的扩展前沿。 我的实验室使用动力学和全基因组工具的有力补充来研究 可以调节核糖体延伸以调节基因表达。我们还直接与专家合作， 研究核糖体和mRNA结构。本建议着重于使用这些方法进行调查 在分子水平上，核糖体的缓慢进展与细胞健康有关， 可行性，但分子机制是未知的。具体来说，我们的工作旨在发现：1）新生 肽调节翻译速率，2）核糖体的非规范运动如何改变基因 表达，3）mRNA修饰如何影响翻译速率，以及4）翻译后修饰如何 影响翻译机器。这些研究将提供一个生物化学框架， 控制核糖体延伸率有助于基因表达的全局性。 总之，我们填补了通过核糖体停滞进行翻译调控这一新兴领域的关键空白 机制等我们的研究将揭示通过翻译停滞的基因调控的广度，并剖析 翻译控制的分子机制。总的来说，这项工作将挑战长期以来的范式， 核糖体以几乎一致的速率不加区别地翻译大部分序列。从长远来看，我们 这一发现可能是开发靶向治疗药物的关键， 翻译延伸

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.