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.

摘要 转移rna(Trna)传统上被认为是帮助核糖体合成的接头分子。 蛋白质是通过解码将mRNA序列连接到蛋白质的氨基酸序列的核苷酸三联体来实现的。近期 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- 派生片段(TRF)。分子生物学中的新兴概念是这些转录因子执行调控 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研究表明，在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)被激活以 以tRNA的反密码子环为靶点，产生特定的TRF亚类，称为tRNA衍生应激- 诱导RNA(TiRNAs)。自2009年发现以来，人们已经发现tiRNAs在压力中发挥作用 适应、细胞存活和凋亡。相对较好地研究了选定的tiRNAs子集的作用之一 (源自tRNAAla和tRNACys)是通过干扰 帽结合络合物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小说的功能，以前 未被探索的，翻译调控中的tiRNAs。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，威尔 采用候选和无偏倚的方法鉴定和鉴定tiRNAs的信使核糖核酸。我们的 初步数据表明，特定的tiRNAs针对特定的mRNAs池，从而对细胞进行重新编程 翻译。通过利用核糖体图谱，我们可以寻找受tiRNAs调控的mrna候选基因。 以公正的方式。 我们的提议具有很高的创新性，将对RNA生物学产生广泛影响。圆满完成 拟议的研究将导致描述在应激过程中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生产的变化有关。在患者中发现影响血管紧张素转换酶核糖核酸酶活性的突变 伴有神经退行性疾病的肌萎缩侧索硬化症和帕金森氏病。另外，Ang是 在多种癌症中过度表达及其表达与tiRNA生产失衡相关，提示 有必要了解tiRNAs的功能。最后，这项建议将为 整个RNA/tRNA社区，我们将确保这些资源可供未来使用。