mRNA selection for translation: beyond the canonical view

用于翻译的 mRNA 选择：超越规范观点

• 批准号: BB/Y005783/1
• 负责人: Mark Peter Ashe
• 金额: $ 124.26万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY005783%2F1
• 关键词: mRNA; selection; translation; beyond; canonical

A central tenet of biology is that information found in the DNA of genes is converted into a messenger RNA molecule (mRNA), which is then translated into a chain of amino acids called a 'protein'. Proteins carry out most biological functions, catalyzing metabolic reactions as well as serving structural and regulatory roles. The complement of mature proteins present in a cell dictate its identity, function and health. Therefore, it is critical to all life that cells have the capacity to control which proteins are produced, when they are produced, their level when produced and their site of production within the cell. Some of the most abundant proteins in the cell such as proteins involved in the production of energy and in the production of proteins themself are often 1000s of times more abundant than other more regulatory proteins. One key stage where these controls are evident is when the machine for producing proteins, termed the ribosome, is recruited to the RNA. Scientists over the last 50 years have gradually pieced together a pathway involving a series of protein factors that are important in the translation of mRNA. More recently they have added the precise structures of the individual molecules within many of these proteins. Overall, this has led to a canonical textbook model for the process of ribosome recruitment to an mRNA that is conserved from yeast to human cells and is called the translation initiation pathway.In our recent work, we have used the relatively simple yeast model system to ask- how well do the 1000s of different mRNA molecules present even in a simpler cell interact with these different translation factors? This work has led to a surprising observation. Many of the mRNAs producing the most abundant proteins in the cell - proteins critical for fundamental pathways of life - interact poorly with these translation factors. This then begs a question- how do these mRNAs that are fundamental to all living systems effectively compete for ribosomes in a sea of other mRNAs? Hence, we started to look at where mRNAs are translated within cells. Again, we were surprised to find that many of the fundamental mRNAs described above are translated at specific sites that have been termed 'translation factories'. It makes sense to produce these proteins in a special place within the cell, as it means the process can be fine-tuned and co-ordinated without interfering with more general production of proteins. However, the rules that decide which mRNAs are translated in a local factory and the protein factors involved in the translation process in these sites are very poorly understood. Therefore, in this proposal, we will determine the molecular rules that enable translation of fundamental heavily translated mRNAs. This will include the RNA sequences and protein factors involved in translation factories, the role of canonical translation factors at these sites, and the importance of these mechanisms for a cell's life. A greater understanding of how cells prioritise the mRNAs that are translated into protein will have immediate applications in the production of medical and commercial proteins - enabling high level expression of valuable proteins, and will also impact upon studies of disease- from diseases where proteins aggregate in cells such as Parkinson's to nutritional diseases associated with deficiencies in particular proteins involved in metabolism.

生物学的中心宗旨是，在基因DNA中发现的信息被转化为信使RNA分子（mRNA），然后将其转化为称为“蛋白质”的氨基酸链。蛋白质发挥大多数生物学功能，催化代谢反应以及发挥结构和调节作用。细胞中存在的成熟蛋白质的补体决定其身份，功能和健康。因此，对所有生命至关重要，细胞具有控制哪些蛋白质产生的能力，当它们产生时，产生时水平以及细胞内的生产部位。细胞中一些最丰富的蛋白质，例如参与能量产生的蛋白质和蛋白质的产生，通常比其他更调节性蛋白更丰富1000倍。这些控制很明显的一个关键阶段是将用于核糖体的蛋白质的机器募集到RNA中。在过去的50年中，科学家逐渐将一条涉及一系列蛋白质因子的途径拼凑在一起，这些因素在mRNA的翻译中很重要。最近，他们在许多这些蛋白质中添加了单个分子的精确结构。总体而言，这导致了一个规范的教科书模型，用于从酵母到人类细胞中保守的核糖体募集过程，被称为翻译起始途径。在我们的最新工作中，我们使用相对简单的酵母模型系统来询问 - 不同mRNA分子的1000s在简单细胞中的1000s在与这些不同的翻译因子中相互作用之间相互作用吗？这项工作导致了令人惊讶的观察。许多在细胞中产生最丰富蛋白质的mRNA-对生命基本途径至关重要的蛋白质与这些翻译因子相互作用很差。然后提出了一个问题 - 这些对所有生命系统至关重要的mRNA如何有效地竞争其他mRNA海洋中的核糖体？因此，我们开始研究在细胞内翻译mRNA的位置。再次，我们惊讶地发现，上述许多基本mRNA都是在被称为“翻译工厂”的特定站点翻译的。在细胞内的一个特殊位置生产这些蛋白质是有意义的，因为这意味着该过程可以进行微调和协调，而不会干扰更多一般的蛋白质产生。但是，确定哪些mRNA在当地工厂中翻译的规则以及这些站点中翻译过程中涉及的蛋白质因素的理解很差。因此，在此提案中，我们将确定能够翻译基本翻译的mRNA的分子规则。这将包括翻译工厂中涉及的RNA序列和蛋白质因子，这些位点的规范翻译因子的作用以及这些机制对细胞寿命的重要性。对细胞如何优先级化为蛋白质的细胞如何在医学和商业蛋白质的产生中立即应用 - 可以高水平表达有价值的蛋白质，并且还将影响来自疾病的疾病的研究，其中蛋白质在蛋白质中的蛋白质聚集在细胞中，例如与帕金森氏症相关的缺乏蛋白质与特定蛋白质相关的营养疾病，这些蛋白质与特定蛋白质相关。