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

在分子水平上理解生物过程仍然是现代最大的挑战之一。除了了解是什么驱使我们前进，基础生物学研究可能有助于人类疾病的治疗或预防，导致农业生产/多样性的增加，支持环境管理，并引发基于生物的新技术的开发。所有细胞生物学过程的中心是遗传信息流，即所谓的基因表达途径。在这个途径中，我们基因的线性DNA序列被复制到一个化学上相似但不太稳定的分子中，称为RNA。这些被称为信使RNA(信使RNA)的短暂基因拷贝然后被输送到称为核糖体的高度专业化的结构中。在这里，编码在信使核糖核酸中的信息被转换成功能蛋白质分子，然后这些分子执行细胞所需的特定过程。这条通路中任何一点的错误都可能对细胞产生非常严重的后果。例如，插入到mRNA序列中的复制错误可能导致蛋白质错误折叠或缩短，从而无法正确执行其功能。基因表达错误经常发生，即使在正常的健康细胞中也是如此。因此，至关重要的是，细胞能够识别错误的mrna分子并有效地摧毁它们。为了监测它们的信使核糖核酸的产生，细胞进化出了许多质量控制系统，统称为信使核糖核酸监测。这些过程确保了错误产生的信使核糖核酸分子被挑选出来并迅速降解，从而防止产生缺陷蛋白质。降解RNA的细胞武器库中的一个主要部分是外切体。外切体由10种不同的酶组成，这些酶在一个复合体中相互关联。包装在一起，这些酶可以比它们自己更有效地工作。该复合体还允许协调调节；所有的酶都可以同时打开或关闭。以前的研究已经确定了外切体复合体的成分，并证明了它在RNA降解中的功能。然而，人们对该建筑群是如何监管的知之甚少。这项研究项目将确定能够促进外切体活性或抑制其活性的蛋白质。然后将研究识别出的蛋白质在依赖于外切体的细胞过程中的功能，例如mRNA监测。对信使核糖核酸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。这些知识将对蛋白质生产的新生物技术战略的设计和开发有潜在的好处。此外，mRNA监测现象与一些普遍存在的人类遗传病的基础直接相关，如乳腺癌。外切体也是一种成功的抗癌药物的生物靶点。因此，了解外切体复合体的活性是如何调节的，可能会为制定未来的疾病治疗或预防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.