The role of RNA-binding proteins in the nucleolar stress response

细胞生物学的核心信条是，细胞中遗传物质中的信息，即DNA，通过中间底物--信使核糖核酸--转化为蛋白质。为了合成蛋白质，mRNA必须与称为核糖体的大型复合体相互作用，核糖体由核糖体RNA(rRNA，它不携带制造特定蛋白质的指令，如mRNAs，而是提供结构并有助于核糖体的活动)和蛋白质组成。核糖体可以被认为是分子工厂，在这里，保存在mRNA中的遗传信息被解码，然后合成成蛋白质。核糖体对于细胞的生长和增殖是必不可少的，对于细胞的分裂和生长来说，核糖体的数量必须增加一倍(以便制造更多的蛋白质)。要做到这一点，必须同时合成组成核糖体的所有蛋白质(大约有80种)，并以正确的数量合成适量的rRNA。核糖核糖核酸是在细胞核内的一个称为核仁的区域内制造的。一种蛋白质，用于读取DNA中的序列，并将它们转化为rRNA，称为聚合酶I(PolI)。当细胞暴露在可能损害它们的外部因素(如阳光或病毒感染后)时，它们会经历一个复杂的过程，在这个过程中，它们会感觉到所造成的损害，细胞中的蛋白质会产生一系列变化，以确保细胞的生存。在此期间，细胞停止生长和分裂，实现这一点的方法之一是通过抑制PolI活性和停止产生核糖体来停止rRNA的产生。当这种情况发生时，核仁被分解，核仁内的蛋白质进入核的其余部分(核质)。虽然核仁中的大多数蛋白质只是制造核糖体所必需的，但其中一些蛋白质还有其他重要的功能。我们的数据和其他人的数据表明，核仁中一些蛋白质的非核糖体功能与细胞对外部因素造成的损伤的反应有关。在这个应用中，我们打算研究这些具有非核糖体功能的蛋白质如何允许细胞对不同类型的损伤做出反应。这些研究的结果可能对设计新的方法来针对与癌症等异常细胞增殖相关的疾病具有重要意义。

The central dogma of cell biology is the information in the genetic material in the cell, the DNA, is converted via an intermediary substrate, mRNA, into proteins. For proteins to be synthesised the mRNA must interact with a large complex called the ribosome which consists of ribosomal RNA (rRNA, which do not carry instructions to make specific proteins like mRNAs but instead provide structure and contribute to the activity of the ribosome) and proteins. Ribosomes can be thought of as molecular factories where the genetic information that is held in the mRNA is decoded and then synthesised into proteins. Ribosomes are essential for cell growth and proliferation and for a cell to divide and grow, it is necessary for the number of ribosomes to double (so that more proteins can be made). For this to occur it is essential that all the proteins that make up the ribosome (there are approximately 80 of these) are made at the same time, in the correct amount and the right amount of rRNA has to be synthesised. The rRNA is made in the nucleus within a compartment that is called the nucleolus. The protein that is used to read the sequences in the DNA and covert them into rRNA in called polymerase I (Pol I). When cells are exposed to external agents that can damage them (such a sunlight or following viral infection), they undergo a complex process where they sense the damage that is caused and the proteins in the cells act to bring about a range changes to ensure the survival of the cell. During this time the cell stops growing and dividing and one of the ways in which this is achieved is by stopping the production of rRNA by inhibition Pol I activity and stopping the production of ribosomes. When this occurs the nucleolus is disassembled and the proteins within the nucleolus enter the rest of the nucleus (the nucleoplasm). While most of the proteins in the nucleolus are simply required to make ribosomes, some of these proteins have important other functions. Our data, and that of others, suggest that non-ribosomal functions of some of the proteins in the nucleolus are associated with the cellular responses to the damage that has been caused to it by external agents. In this application we propose to study how these proteins with non-ribosomal functions allow the cell to respond to different types of injury. The results obtained from these studies could have important implications for devising new ways in which to target disease that are associated with aberrant cell proliferation such as cancers.