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.

概括 传统上将转移RNA（tRNA）视为有助于核糖体合成的衔接子分子 蛋白质通过解码将mRNA序列与蛋白质氨基酸序列联系起来的核苷酸三重态。最近的 调查结果表明，TRNA也是小型非编码RNA的主要来源，所谓的tRNA衍生 片段（TRF）。分子生物学的新兴概念是这些TRF执行调节功能， 尽管对它们在细胞生理学中的精确作用知之甚少。 我们和其他实验室的工作表明，响应各种非生物应力（例如 氧化物或养分应激），脊椎动物特异性核糖核酸酶（RNase）血管生成蛋白（ANG）被激活至靶 TRNA的反登陆环路产生特定的TRF，称为TRNA衍生应力诱导的 RNA（TIRNA）。自2009年发现以来，已经发现TIRNA在压力适应中起着作用 生存和凋亡。 TIRNA选定子集的相对良好研究的作用之一（源自trnaala 和trnacys）是通过干扰帽结合复合物eIF4F的功能来抑制翻译计划 （Ivanov等人，Mol Cell 2011）。 该提案将进一步研究新颖的，以前出乎意料的TIRNA在调节中的功能 翻译。我们的初步数据表明，存在翻译调制的替代机制是 与Tirnaala/Cys使用的机制不同。在AIM1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 - 特定的TIRNA使用重叠的机制介导抑制和刺激mRNA 翻译。在AIM 2中，我们将通过聘用候选人和 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TIRNA目标 mRNA的特定池因此重新编程了细胞翻译。 我们的建议具有很高的创新性，将广泛影响RNA生物学。成功完成 拟议的研究将导致表征应力期间作用的新型翻译控制机制。 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生产的变化有关。在患者中发现影响ANG的RNase活性的突变 神经退行性疾病肌萎缩性侧索硬化和帕金森氏病。另外，Ang是过度的 在多种癌症中表达，其表达与tirna的失误相关，表明 必须了解Tirnas的功能。最后，该建议将为整个资源生成许多资源 RNA/tRNA社区，我们将确保这些资源可用于将来使用。