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Dissecting mechanisms of mRNA translational control by specialised ribosomes

剖析特殊核糖体控制 mRNA 翻译的机制

基本信息

批准号：
2426757
负责人：
金额：
--
依托单位：
University of Leeds
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2426757
关键词：
Dissecting mechanisms mRNA translational control

项目摘要

The average cell contains ~10 million ribosomes, comprised of ~80 ribosomal proteins and 4 rRNAs. Until recently it was thought that all ribosomes were the same. But substantial new evidence has revealed that ribosome heterogeneity provides an additional level of translational control. These different ribosome populations are termed 'specialised ribosomes'. How these specialised ribosomes translate specific mRNA pools remains a mystery. This project aims to understand how changes in ribosome composition enable translation of specific mRNA pools by altered ribosome structures.We have discovered differences in ribosome composition in Drosophila melanogaster brain and testis (project currently funded by a BBSRC grant). mRNA translation is particularly important during sperm production and neural function so it will be exciting to understand how this novel mechanism of gene regulation is achieved.Using a cutting-edge combination of translatomics and structural biology this project will uncover the function and mechanism of specialised ribosomes. We will determine which mRNAs specialised ribosomes translate using Ribo-Seq (Next Generation Sequencing) and how specialisation is achieved using cryo-EM. These approaches are data intensive and represent priority bioscience skills areas, as both involve large data sets and bioinformatic analysis. This work has potential to shed light on the underlying mechanism of human diseases caused by mutations to ribosomal proteins e.g. Diamond-Blackfan.

平均每个细胞含有约1000万个核糖体，由约80个核糖体蛋白和4个rRNA组成。直到最近，人们还认为所有的核糖体都是一样的。但大量的新证据表明，核糖体异质性提供了额外的翻译控制水平。这些不同的核糖体群体被称为“特化核糖体”。这些专门的核糖体如何翻译特定的mRNA池仍然是一个谜。本项目旨在了解核糖体组成的变化如何通过改变核糖体结构来翻译特定的mRNA库。我们发现了黑腹果蝇大脑和睾丸中核糖体组成的差异（目前由BBSRC资助的项目）。mRNA翻译在精子生成和神经功能中尤为重要，因此了解这种新的基因调控机制是如何实现的将是令人兴奋的。该项目将利用翻译组学和结构生物学的前沿组合，揭示特定核糖体的功能和机制。我们将确定哪些mRNA专门使用Ribo-Seq（下一代测序）翻译核糖体，以及如何使用cryo-EM实现专业化。这些方法是数据密集型的，代表了优先生物科学技能领域，因为两者都涉及大型数据集和生物信息学分析。这项工作有可能揭示由核糖体蛋白突变引起的人类疾病的潜在机制，例如Diamond-Blackfan。