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.

生物学的一个中心原则是，基因DNA中的信息被转化为信使RNA分子（mRNA），然后被翻译成称为“蛋白质”的氨基酸链。蛋白质执行大多数生物功能，催化代谢反应以及充当结构和调节角色。存在于细胞中的成熟蛋白质的补充决定了其身份，功能和健康。因此，对所有生命来说至关重要的是，细胞有能力控制产生哪些蛋白质，何时产生，产生时的水平及其在细胞内的产生部位。细胞中一些最丰富的蛋白质，如参与能量生产的蛋白质和蛋白质本身的生产，通常比其他更具调节性的蛋白质丰富1000倍。这些控制很明显的一个关键阶段是当生产蛋白质的机器，称为核糖体，被招募到RNA。在过去的50年里，科学家们逐渐拼凑出一条涉及一系列蛋白质因子的通路，这些蛋白质因子在mRNA的翻译中非常重要。最近，他们在许多蛋白质中加入了单个分子的精确结构。总的来说，这为核糖体募集到mRNA的过程提供了一个经典的教科书模型，该过程从酵母到人类细胞都是保守的，称为翻译起始途径。在我们最近的工作中，我们使用了相对简单的酵母模型系统来询问--即使在更简单的细胞中，一千个不同的mRNA分子的存在程度如何与这些不同的翻译因子相互作用？这项工作导致了一个令人惊讶的观察。许多产生细胞中最丰富的蛋白质（对生命的基本途径至关重要的蛋白质）的mRNA与这些翻译因子的相互作用很差。这就引出了一个问题--这些对所有生命系统都至关重要的mRNA如何在其他mRNA的海洋中有效地竞争核糖体？因此，我们开始研究mRNA在细胞内的翻译位置。再次，我们惊讶地发现，上述许多基本mRNA在被称为“翻译因子”的特定位点翻译。在细胞内的一个特殊位置产生这些蛋白质是有意义的，因为这意味着这个过程可以被微调和协调，而不会干扰更一般的蛋白质生产。然而，决定哪些mRNA在本地工厂中翻译的规则以及这些位点中参与翻译过程的蛋白质因子知之甚少。因此，在本提案中，我们将确定使基本的大量翻译的mRNA翻译的分子规则。这将包括参与翻译工厂的RNA序列和蛋白质因子，这些位点的典型翻译因子的作用，以及这些机制对细胞生命的重要性。更好地理解细胞如何优先考虑翻译成蛋白质的mRNA将直接应用于医疗和商业蛋白质的生产-使有价值的蛋白质的高水平表达成为可能，并且还将影响疾病的研究-从蛋白质在细胞中聚集的疾病，如帕金森氏症到与参与代谢的特定蛋白质缺乏相关的营养性疾病。