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

RNA结合蛋白在核仁应激反应中的作用

• 批准号: BB/M006700/1
• 负责人: Anne Willis
• 金额: $ 32.9万
• 依托单位: MRC Toxicology Unit
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM006700%2F1
• 关键词: role; RNA; binding; proteins; nucleolar

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.

细胞生物学的中心法则是细胞中遗传物质的信息，即DNA，通过中间底物mRNA转化为蛋白质。对于要合成的蛋白质，mRNA必须与称为核糖体的大型复合物相互作用，核糖体由核糖体RNA（rRNA，其不携带制造特定蛋白质的指令，如mRNA，而是提供结构并有助于核糖体的活性）和蛋白质组成。核糖体可以被认为是分子工厂，其中mRNA中的遗传信息被解码，然后合成为蛋白质。核糖体对于细胞生长和增殖是必不可少的，对于细胞分裂和生长，核糖体的数量必须加倍（以便可以制造更多的蛋白质）。要做到这一点，必须同时合成正确数量的所有组成核糖体的蛋白质（大约有80种），并且必须合成正确数量的rRNA。rRNA是在细胞核中一个叫做核仁的隔间中产生的。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）。当细胞暴露于可能损害它们的外部因素（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，细胞中的蛋白质会产生一系列变化，以确保细胞的存活。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Pol I活性和停止核糖体的产生来停止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因素造成的损伤的反应有关。在本申请中，我们建议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。从这些研究中获得的结果可能对设计靶向与异常细胞增殖相关的疾病（如癌症）的新方法具有重要意义。

项目成果

Cap-Independent Translation in Hematological Malignancies.

• DOI: 10.3389/fonc.2015.00293
• 发表时间: 2015
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Horvilleur E;Wilson LA;Bastide A;Piñeiro D;Pöyry TA;Willis AE
• 通讯作者: Willis AE

Identification of the RNA polymerase I-RNA interactome.

• DOI: 10.1093/nar/gky779
• 发表时间: 2018-11-16
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Piñeiro D;Stoneley M;Ramakrishna M;Alexandrova J;Dezi V;Juke-Jones R;Lilley KS;Cain K;Willis AE
• 通讯作者: Willis AE

Trans-acting translational regulatory RNA binding proteins.

• DOI: 10.1002/wrna.1465
• 发表时间: 2018-05
• 期刊: Wiley interdisciplinary reviews. RNA
• 作者: Harvey RF;Smith TS;Mulroney T;Queiroz RML;Pizzinga M;Dezi V;Villenueva E;Ramakrishna M;Lilley KS;Willis AE
• 通讯作者: Willis AE

Efficient recovery of the RNA-bound proteome and protein-bound transcriptome using phase separation (OOPS).

• DOI: 10.1038/s41596-020-0344-2
• 发表时间: 2020-08
• 期刊: Nature protocols
• 影响因子: 14.8
• 作者: Villanueva E;Smith T;Queiroz RML;Monti M;Pizzinga M;Elzek M;Dezi V;Harvey RF;Ramakrishna M;Willis AE;Lilley KS
• 通讯作者: Lilley KS

Gemin5: A Multitasking RNA-Binding Protein Involved in Translation Control.

• DOI: 10.3390/biom5020528
• 发表时间: 2015-04-17
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Piñeiro D;Fernandez-Chamorro J;Francisco-Velilla R;Martinez-Salas E
• 通讯作者: Martinez-Salas E