Identification and analysis of factors that regulate the activity of the yeast exosome complex of exoribonucleases

在分子水平上了解生物过程仍然是现代最大的挑战之一。除了了解是什么让我们打勾，基础生物学研究可以帮助治疗或预防人类疾病，导致增加农业生产/多样性，支持环境管理，并引发新的生物技术的发展。所有细胞生物学过程的中心是遗传信息通过所谓的基因表达途径的流动。在这条途径中，我们基因的线性DNA序列被复制到一种化学上相似但不太稳定的分子中，称为RNA。这些短暂的基因拷贝，称为信使RNA（mRNA），然后被运送到称为核糖体的高度专门化的结构。在这里，mRNA中编码的信息被转化为功能性蛋白质分子，然后进行细胞中所需的特定过程。在这条通路中的任何一点上的错误都可能对细胞产生非常严重的后果。例如，插入mRNA序列中的复制错误可能导致错误折叠或缩短的蛋白质无法正确执行其功能。基因表达的错误经常发生，即使在正常健康的细胞中也是如此。因此，细胞必须能够识别有缺陷的mRNA分子并有效地破坏它们。为了监测mRNA的产生，细胞已经进化出许多质量控制系统，统称为mRNA监视。这些过程确保不正确产生的mRNA分子被选择出来并迅速降解，从而防止有缺陷的蛋白质的产生。细胞降解RNA的主要武器是外泌体。外泌体由10种不同的酶组成，这些酶在复合体中相互关联。将这些酶包装在一起，可以比它们自己更有效地工作。该复合物还允许协调调节;所有酶可以同时打开或关闭。以前的研究已经确定了外泌体复合物的组分，并证明了其在RNA降解中的功能。然而，人们对这种复合物是如何调节的知之甚少。该研究项目将鉴定起促进外泌体活性或抑制其活性作用的蛋白质。然后将研究所鉴定的蛋白质在外泌体依赖性细胞过程如mRNA监视中的功能。对mRNA监测的进一步研究将增加我们对细胞中基因表达如何控制的理解。这方面的知识将是潜在的好处，在设计和开发新的生物技术战略的蛋白质生产。此外，mRNA监视现象与一些流行的人类遗传疾病（如乳腺癌）的基础直接相关。外泌体也是成功抗癌药物的生物靶点。因此，了解外泌体复合物的活性是如何调节的，可以为开发疾病治疗或预防的未来策略提供重要的信息来源。

Understanding biological processes at the molecular level remains one of the greatest challenges of the modern age. In addition to understanding what makes us tick, fundamental biological research can potentially aid the treatment or prevention of human diseases, lead to increased agricultural production/diversity, support environment management and trigger the development of new biology-based technologies. Central to all cellular biological processes is the flow of genetic information through what is known as the gene expression pathway. In this pathway, the linear DNA sequence of our genes is copied into a chemically similar but less stable molecule, called RNA. These short-lived gene copies, known as messenger RNA (mRNA), are then transported to highly specialised structures called ribosomes. Here, the information encoded within the mRNA is converted into functional protein molecules, which then carry out the specific processes required in the cell. A mistake at any point within this pathway can have very serious consequences for the cell. For example, a copying error inserted into the mRNA sequence can result in an incorrectly folded or shortened protein that is unable to perform its function correctly. Mistakes in gene expression occur rather often, even in normal, healthy cells. Therefore, it is essential that cells are able to recognise faulty mRNA molecules and destroy them efficiently. To monitor the production of their mRNA, cells have evolved a number of quality control systems that are known collectively as mRNA surveillance. These processes ensure that incorrectly produced mRNA molecules are selected out and rapidly degraded, thereby preventing the production of defective proteins. A major piece of the cell's armoury for degrading RNA is the exosome. The exosome consists of 10 different enzymes associated with one another in a complex. Packaged together, these enzymes can work more efficiently than they could on their own. The complex also allows coordinated regulation; all the enzymes can be switched on or swiched off at the same time. Previous studies have identified the components of the exosome complex and demonstrated its function in RNA degradation. However, little is known about how the complex is regulated. This research project will identify proteins that function either to promote the activity of the exosome or to inhibit its activity. The function of the identified proteins in exosome-dependent cellular processes such as mRNA surveillance will then be studied. Further studies on mRNA surveillance will increase our understanding of how gene expression is controlled in the cell. This knowledge will be of potential benefit in the design and development of new biotechnological strategies for protein production. Moreover, mRNA surveillance phenomena are directly linked to the basis of some prevalent human genetic disorders, such as breast cancer. The exosome is also a biological target of a successful anti-cancer drug. Hence, a knowledge of how the activity of the exosome complex is regulated may provide an important resource of information in developing future strategies in the treatment or prevention of disease.