Quality control of gene expression - RNA surveillance

基因表达的质量控制 - RNA 监测

• 批准号: BB/F010281/1
• 负责人: Helen Saibil
• 金额: $ 19.54万
• 依托单位: Birkbeck, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF010281%2F1
• 关键词: Quality; control; gene; expression; RNA

The exosome is a large multisubunit complex endowed with exonuclease activity. This nuclease is the major 3'-5' exonuclease of eukaryotic cells. It is constituted of a core containing 10 different proteins to which associate nuclear and cytoplasmic specific subunits. The exosome has been implicated in most decay pathways involved in the removal of aberrant and non-functional RNA molecules. Those include elimination of Cryptic Unstable Transcrips (CUTs), aberrant tRNAs, non-spliced pre-mRNA as well as some snRNAs and rRNAs in the nucleus. In the cytoplasm, the exosome has been show to degrade non-functional mRNAs containing a premature stop codon (NMD), those lacking a stop codon (NSD) or those provoking ribosome stalling (No-Go decay). The exosome thus plays a central and essential role in the control of RNA quality. The exosome has to target and degrade aberrant RNAs without attacking functional molecules. This discrimination results in part from the action of factors that will bind and/or modify biologically relevant substrates and target them to degradation. Such factors include the Trf/Air poly(A) polymerase and Mtr4 DEAD box helicase in the nucleus and the Ski7 GTpase and Ski2/3/8 complex in the cytoplasm. If the enzymes and factors involved in these pathways are known, the mechanisms leading them to selectively degrade aberrant RNA molecules remain unclear. We propose here a multidisciplinary study of the role of the exosome in RNA quality control pathways. This analysis will combine molecular biology and biochemical approaches, native mass spectrometry, structural analyses by electron microscopy and small angle X-ray scattering to provide a structural and functional framework allowing the understanding of the role of the exosome in RNA surveillance. We envision that the methodology, developed in this collaborative project involving experts in complementary fields, will be useful to study other RNA based processes and other molecular mechanisms in the future.

外切体是一种具有核酸外切酶活性的多亚基复合体。这种核酸酶是真核细胞的主要3 '-5'核酸外切酶。它由含有10种不同蛋白质的核心组成，这些蛋白质与细胞核和细胞质特异性亚基相关。外泌体与大多数涉及去除异常和非功能RNA分子的衰变途径有关。这些包括消除隐藏的不稳定转录本（CUT），异常的tRNA，非剪接的前mRNA以及细胞核中的一些snRNA和rRNA。在细胞质中，外泌体已显示降解含有提前终止密码子（NMD）的非功能性mRNA、缺乏终止密码子（NSD）的那些或引起核糖体停滞（No-Go衰变）的那些。因此，外泌体在控制RNA质量中起着核心和重要的作用。外泌体必须在不攻击功能分子的情况下靶向并降解异常RNA。这种区分部分是由于结合和/或修饰生物相关底物并使其降解的因子的作用。这些因子包括细胞核中的Trf/Air poly（A）聚合酶和Mtr 4 DEAD box解旋酶以及细胞质中的Ski 7 GTP酶和Ski 2/3/8复合物。如果参与这些途径的酶和因子是已知的，那么导致它们选择性降解异常RNA分子的机制仍不清楚。我们在这里提出了一个多学科的研究外泌体在RNA质量控制途径中的作用。该分析将结合联合收割机分子生物学和生物化学方法、天然质谱法、电子显微镜结构分析和小角X射线散射，以提供允许理解外泌体在RNA监视中的作用的结构和功能框架。我们设想，在这个合作项目中开发的方法，涉及互补领域的专家，将有助于研究其他RNA为基础的过程和其他分子机制的未来。

项目成果

Newly folded substrates inside the molecular cage of the HtrA chaperone DegQ.

• DOI: 10.1038/nsmb.2210
• 发表时间: 2012-01-15
• 期刊: NATURE STRUCTURAL & MOLECULAR BIOLOGY
• 影响因子: 16.8
• 作者: Malet, Helene;Canellas, Flavia;Sawa, Justyna;Yan, Jun;Thalassinos, Konstantinos;Ehrmann, Michael;Clausen, Tim;Saibil, Helen R.
• 通讯作者: Saibil, Helen R.

Structure of a type IV secretion system core complex.

• DOI: 10.1126/science.1166101
• 发表时间: 2009-01-09
• 期刊: Science (New York, N.Y.)
• 作者: Fronzes R;Schäfer E;Wang L;Saibil HR;Orlova EV;Waksman G
• 通讯作者: Waksman G