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: 10797061
• 负责人: Pavel Ivanov
• 金额: $ 3.63万
• 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/10797061
• 关键词: Affect; Alanine-Specific tRNA; Amyotrophic Lateral Sclerosis; Anticodon; Apoptosis; Binding; Biogenesis; Biology; Cell Survival; Cell physiology; Cells; Communities; Complex; Cysteine-Specific tRNA; Data; Employment; Ensure; Funding; Future; Gene Expression Regulation; Laboratories; Link; Malignant Neoplasms; Messenger RNA; Molecular; Molecular Biology; Mutation; Neurodegenerative Disorders; Nucleotides; Nutrient; Parkinson Disease; Pathway interactions; Patients; Play; Production; Protein Biosynthesis; RNA; Resources; Ribonucleases; Role; Source; Stress; Therapeutic; Transfer RNA; Translation Initiation; Translational Regulation; Translational Repression; Translations; Triplet Multiple Birth; Untranslated RNA; Work; angiogenin; human disease; innovation; novel; overexpression; protein aminoacid sequence; response; ribosome profiling

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). The work based on our funded 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. Aim 2 of the R01, will identify and characterize mRNA targets of tiRNAs by employing candidate and unbiased approaches. Our preliminary data suggest that specific tiRNAs target specific pool of mRNAs thus reprogramming cellular translation. By employment of ribosome profiling, we can search for the mRNA candidates regulated by tiRNAs in unbiased manner. 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 转移 RNA (tRNA) 传统上被视为帮助核糖体合成的衔接分子 通过解码将 mRNA 序列与蛋白质氨基酸序列连接的核苷酸三联体来识别蛋白质。最近的 研究结果表明，tRNA 也是小非编码 RNA（所谓的 tRNA-）的主要来源。 衍生片段（tRF）。分子生物学中的新兴概念是这些 tRF 执行调节作用 功能，尽管人们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，为了应对各种非生物胁迫（例如， 氧化或营养应激），脊椎动物特异性核糖核酸酶（RNase）血管生成素（ANG）被激活 靶向 tRNA 的反密码子环，产生特定的 tRF 亚类，称为 tRNA 衍生应激- 诱导RNA（tiRNA）。自 2009 年被发现以来，tiRNA 被发现在压力中发挥作用 适应、细胞存活和凋亡。选定的 tiRNA 子集的研究相对充分的作用之一 （源自 tRNAAla 和 tRNACys）通过干扰 帽结合复合物 eIF4F（Ivanov 等人，Mol Cell 2011）。 基于我们资助的提案的工作将进一步研究以前新颖的功能 未经探索的 tiRNA 在翻译调控中的作用。我们的初步数据表明，替代机制 存在与 tiRNAAla/Cys 使用的机制不同的翻译调制。 R01 的目标 2 将 通过采用候选和公正的方法来识别和表征 tiRNA 的 mRNA 靶标。我们的 初步数据表明，特定的 tiRNA 靶向特定的 mRNA 库，从而重新编程细胞 翻译。通过核糖体分析，我们可以寻找受tiRNA调控的mRNA候选物 以公正的方式。 我们的提案具有高度创新性，将广泛影响 RNA 生物学。圆满完成了 拟议的研究将导致在压力期间发挥作用的新型翻译控制机制的特征。 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 RNase 活性的突变 与神经退行性疾病肌萎缩侧索硬化症和帕金森病有关。另外，ANG 是 在多种癌症中过度表达，其表达与 tiRNA 产生失衡相关，表明 了解 tiRNA 功能的必要条件。最后，该提案将为 整个 RNA/tRNA 社区，我们将确保这些资源可供未来使用。