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 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连接的核苷酸三重态。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- 派生的片段（TRF）。分子生物学的新兴概念是这些TRF执行调节性 功能虽然对它们在细胞生理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）被激活至 靶向TRNA的反登陆环路，以产生特定的TRF子类，称为TRNA衍生应力 - 诱导RNA（TIRNA）。自2009年发现以来，已经发现Tirnas在压力中起着作用 适应，细胞存活和凋亡。 TIRNA选定子集的相对精心研究的角色之一 （源自trnaala和trnacys）是通过干扰对翻译起始的抑制 盖结合复合物EIF4F（Ivanov等人Mol Cell 2011）。 基于我们资助的建议的工作将进一步研究新颖的功能，以前 未开发的TIRNA在翻译调节中。我们的初步数据表明 存在与Tirnaala/Cys使用的机制不同的翻译调制。 R01的目标2 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池因此重新编程了细胞 翻译。通过使用核糖体分析，我们可以搜索受TIRNA调节的mRNA候选者 以公正的方式。 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症和帕金森氏病。另外，Ang是 在多种癌症中过表达，其表达与蒂尔纳（Tirna）的生产失误相关，表明 理解TIRNA功能的必要性。最后，该建议将为 整个RNA/tRNA社区，我们将确保这些资源可用于将来使用。