The Nucleolar Detention Center: a Hub of Long Noncoding RNAs that Imprison Protei

 描述（申请人提供）：核仁滞留中心：在压力期间监禁蛋白质的长非编码RNA的枢纽（注：引用了我们小组的论文）项目概述细胞适应各种压力条件的能力在各种病理生理学环境中起着关键作用，包括发育，癌症和神经系统疾病。我们最近报道了一个意外的发现，应激诱导的长非编码RNA来源于核糖体基因间间隔区的刺激特异性位点（Mol. Cell（2012）45：147），假定为转录失活的人类基因组的神秘区域。基因间间隔区RNA（IGSRNA）的诱导将核仁从核糖体工厂转化为核仁滞留中心：响应于细胞外应激物而滞留特定蛋白质的分子监狱（Nature Cell Biol.（2004）6：642; J.Cell.（2005）170：733; Mol.生物细胞（2013）24：2943）。IGSRNAs通过与核仁滞留序列（NoDS）相互作用捕获和抑制核仁滞留中心中的蛋白质，NoDS是一种调节蛋白质流动性的离散肽代码（Mol.（2007）19：3966）。我们将展示的初步数据，rDNA基因间间隔区产生一系列新的和复杂的IGSRNAs，限制在核仁内不同的蛋白质组，这取决于环境的线索。这使得细胞能够通过暂时阻止关键途径（包括DNA复制、转录、翻译和蛋白质降解）来定制它们对各种不利条件的生物反应。基于上述理论，我们提出以下假设：IGSRNAs通过捕获和固定核仁滞留中心的不同蛋白质来诱导细胞对环境应激的适应。在具体目标中，我们将：1-破译核糖体基因间间隔区作为lncRNA响应环境线索的枢纽; 2-揭示刺激特异性核仁滞留中心; 3-探索应激特异性IGSRNA诱导的核仁滞留的生物学和生化后果。IGSRNA调节的核仁滞留途径的发现为研究细胞应激反应中涉及的大量未探索的翻译后机制打开了一扇独特而非凡的机会之窗。IGSRNA导向通路的研究将产生重大的概念性进展，我们的理解关键的适应性/抵抗过程中遇到的细胞，如酸性肿瘤微环境，高热，暴露于抗癌药物。

 DESCRIPTION (provided by applicant): The Nucleolar Detention Center: a Hub of Long Noncoding RNAs that Imprison Proteins During Stress (Note: papers from our group are cited) PROJECT SUMMARY The ability of cells to adapt to a wide variety of stress conditions plays a critical role in various pathophysiological settings, including development, cancer and neurological disorders. We recently reported the unexpected discovery of stress-induced long noncoding RNAs derived from stimuli-specific loci of the ribosomal intergenic spacer (Mol. Cell (2012) 45:147), an enigmatic region of the human genome assumed to be transcriptionally inactive. Induction of intergenic spacer RNA (IGSRNA) converts the nucleolus from a factory of ribosomes to the nucleolar detention center: a molecular prison that detains specific proteins in response to extracellular stressors (Nature Cell Biol. (2004) 6:642; J.Cell. Biol. (2005) 170:733; Mol. Biol. Cell. (2013) 24: 2943). IGSRNAs capture and immobilize proteins in the nucleolar detention center by interacting with the Nucleolar Detention Sequence (NoDS), a discrete peptide code that regulates protein mobility (Mol. Biol. Cell (2007) 19:3966). We will show preliminary data that the rDNA intergenic spacer produces an array of novel and complex IGSRNAs that confine within the nucleolus distinct groups of proteins, depending upon environment cues. This enables cells to tailor their biological response to various adverse conditions by temporarily arresting critical pathways including DNA replication, transcription, translation and protein degradation. Based on these aforementioned rationales, we propose the following hypothesis: IGSRNAs induce cellular acclimatization to environmental stressors by capturing and immobilizing distinct proteins in the nucleolar detention center. In the Specific Aims, we will: 1- decipher the ribosomal intergenic spacer as a hub of lncRNAs responsive to environmental cues; 2- uncover the stimuli-specific nucleolar detention centers; 3- explore the biological and biochemical consequences of stress-specific IGSRNA-induced nucleolar detention. The discovery of the IGSRNA-regulated nucleolar detention pathway opens a unique and remarkable window of opportunity to investigate a largely unexplored post-translational mechanism involved in the cellular stress response. Study of the IGSRNA-directed pathway will yield significant conceptual advances in our understanding of critical adaptive/resistance processes to stressors encounter by cells, such as the acidotic tumor microenvironment, hyperthermia, and exposure to anti-cancer drugs.