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

细胞生物学的中心法则是细胞中遗传物质DNA中的信息通过中间底物mRNA转化为蛋白质。为了合成蛋白质，mRNA必须与一种叫做核糖体的大复合体相互作用，核糖体由核糖体RNA （rRNA，它不携带制造mRNA等特定蛋白质的指令，而是提供结构并促进核糖体的活性）和蛋白质组成。核糖体可以被认为是分子工厂，在那里，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，核糖体的数量必须翻倍（以便制造更多的蛋白质）。要做到这一点，组成核糖体的所有蛋白质（大约有80种）必须同时合成，并且数量正确，同时必须合成适量的rRNA。rRNA是在细胞核中被称为核仁的隔室中制造的。用于读取DNA序列并将其转化为rRNA的蛋白质称为聚合酶I （Pol I）。当细胞暴露于可以破坏它们的外部因素（如阳光或病毒感染）时，它们会经历一个复杂的过程，在这个过程中，它们会感知到所造成的损害，细胞中的蛋白质会采取行动，带来一系列变化，以确保细胞的生存。在这段时间内细胞停止生长和分裂其中一种方法是通过抑制Pol I活性来停止rRNA的产生并停止核糖体的产生。当这种情况发生时，核仁被分解，核仁内的蛋白质进入细胞核的其余部分（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，但其中一些蛋白质具有重要的其他功能。我们的数据和其他人的数据表明，核仁中某些蛋白质的非核糖体功能与细胞对外部介质对其造成的损伤的反应有关。在这个应用中，我们建议研究这些具有非核糖体功能的蛋白质如何使细胞对不同类型的损伤作出反应。从这些研究中获得的结果可能对设计针对与异常细胞增殖（如癌症）相关的疾病的新方法具有重要意义。

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.