tRNA-derived stress-induced RNAs and translational control

tRNA 衍生的应激诱导 RNA 和翻译控制

• 批准号: 10709543
• 负责人: Pavel Ivanov
• 金额: $ 35.8万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709543
• 关键词: Address; Affect; Alanine-Specific tRNA; Amyotrophic Lateral Sclerosis; Anticodon; Apoptosis; Base Sequence; Binding; Biogenesis; Biological Process; Biology; CRISPR/Cas technology; Cell Survival; Cell physiology; Cells; Cellular Stress; Communities; Complex; Custom; Cytoprotection; Data; Disease; Elements; Ensure; Future; Gene Expression; Gene Expression Regulation; Goals; Health; Human; Human Pathology; Immunity; In Vitro; Investigation; Knowledge; Laboratories; Link; Malignant Neoplasms; Mediating; Messenger RNA; Methods; Modeling; Molecular; Molecular Biology; Mutation; Neurodegenerative Disorders; Nucleotides; Nutrient; Parkinson Disease; Pathology; Pathway interactions; Patients; Play; Postdoctoral Fellow; Process; Production; Property; Protein Biosynthesis; Proteins; Proteomics; RNA; RNA Interference; Reagent; Regulator Genes; Research; Research Personnel; Resources; Ribonucleases; Ribosomes; Role; Signal Transduction; Source; Stress; Structure; System; Technology; Testing; Therapeutic; Transcript; Transfer RNA; Translation Initiation; Translational Regulation; Translational Repression; Translations; Triplet Multiple Birth; Untranslated RNA; Work; angiogenin; biological adaptation to stress; cohort; human disease; innovation; insight; mRNA Translation; new therapeutic target; novel; novel therapeutics; overexpression; programs; protein aminoacid sequence; response; ribosome profiling; targeted treatment

Summary Transfer RNA (tRNA) is traditionally viewed as an adaptor molecule that helps ribosomes synthesize proteins by decoding nucleotide triplets linking mRNA sequence to amino acid sequence of protein. Recent findings demonstrate that tRNAs also serve as a major source of small non-coding RNAs, so called tRNA-derived fragments (tRFs). The emerging concept in molecular biology is that these tRFs perform regulatory functions, although relatively little is known about their precise roles in cell physiology. Work from our and other laboratories has shown that in response to a variety of abiotic stresses (e.g. oxidative or nutrient stress), the vertebrate-specific ribonuclease (RNase) angiogenin (ANG) is activated to target the anticodon loops of tRNAs to produce a specific subclass of tRFs, known as tRNA-derived stress-induced RNAs (tiRNAs). Since their discovery in 2009, tiRNAs have been found to play roles in stress adaptation, cell survival and apoptosis. One of the relatively well studied roles of selected subset of tiRNAs (derived from tRNAAla and tRNACys) is inhibition of translation initiation via interference with functions of the cap-binding complex eIF4F (Ivanov et al. Mol Cell 2011). This proposal will further investigate functions of novel, previously unexplored, tiRNAs in regulation of translation. Our preliminary data suggest that alternative mechanisms of translation modulation exist that are different from the mechanisms used by tiRNAAla/Cys. In Aim1, we will dissect the molecular mechanisms of tiRNA- mediated regulation of translation. Our preliminary data strongly support a model in which multiple non- overlapping mechanisms are used by specific tiRNAs to mediate both inhibition and stimulation of mRNA translation. In Aim 2, we will identify and characterize mRNA targets of tiRNAs by employing candidate and unbiased proteomic and ribosome profiling approaches. Our preliminary data suggest that specific tiRNAs target specific pool of mRNAs thus reprogramming cellular translation. Our proposal is highly innovative and will broadly impact RNA biology. Successful completion of the proposed studies will result in characterization of novel translational control mechanisms acting during stress. Our studies are also important from a therapeutic point of view because multiple pathophysiological conditions are linked to changes in tiRNA production. Mutations affecting the RNase activity of ANG are found in patients with the neurodegenerative diseases Amyotrophic Lateral Sclerosis and Parkinson’s disease. Also, ANG is over- expressed in multiple cancers and its expression correlates with misbalanced tiRNA production, indicating a necessity to understand the function of tiRNAs. Finally, this proposal will generate many resources for the entire RNA/tRNA community and we will ensure that these resources are available for future use.

总结 转运RNA（tRNA）传统上被认为是帮助核糖体合成的衔接分子 通过解码连接mRNA序列和蛋白质氨基酸序列的核苷酸三联体来编码蛋白质。最近 研究结果表明，tRNA也是小的非编码RNA的主要来源，即所谓的tRNA衍生物。 片段（tRFs）。分子生物学中的新兴概念是这些tRF执行调节功能， 尽管对它们在细胞生理学中的确切作用知之甚少。 我们和其他实验室的工作表明，在应对各种非生物胁迫（例如 在氧化或营养应激）时，脊椎动物特异性核糖核酸酶（RNase）血管生成素（ANG）被激活以靶向 tRNA的反密码子环产生一个特定的tRFs亚类，称为tRNA衍生的应激诱导 RNA（tiRNA）。自2009年被发现以来，已经发现tiRNAs在应激适应、细胞凋亡和细胞凋亡中发挥作用。 存活和凋亡。选择的tiRNAs亚组（来源于tRNAAla）的相对充分研究的作用之一是， 和tRNACys）是通过干扰帽结合复合物eIF 4F的功能来抑制翻译起始 （Ivanov等人，Mol Cell 2011）。 该建议将进一步研究新的，以前未探索的，tiRNAs在调节细胞凋亡中的功能。 翻译.我们的初步数据表明，翻译调制的替代机制存在， 与tiRNAAla/Cys使用的机制不同。在Aim 1中，我们将剖析tiRNA的分子机制- 介导的翻译调节。我们的初步数据强烈支持一个模型，其中多个非- 特异性tiRNAs使用重叠机制介导mRNA的抑制和刺激 翻译.在目标2中，我们将通过使用候选的和 无偏的蛋白质组学和核糖体分析方法。我们的初步数据表明，特定的tiRNAs靶向 特定的mRNA库，从而重新编程细胞翻译。 我们的建议是高度创新的，将广泛影响RNA生物学。成功完成 所提出的研究将导致表征在应激期间起作用的新的翻译控制机制。 从治疗的角度来看，我们的研究也很重要，因为多种病理生理条件 与tiRNA产生的变化有关。在患者中发现影响ANG RNA酶活性的突变 患有神经退行性疾病肌萎缩性侧索硬化症和帕金森病。而且，ANG已经结束了- 在多种癌症中表达，并且其表达与不平衡的tiRNA产生相关，表明 了解TIRNAs功能的必要性最后，这一建议将为整个国家带来许多资源， RNA/tRNA社区，我们将确保这些资源可供未来使用。