Ribosomal RNA methylation regulation of longevity and stress resistance

核糖体RNA甲基化对长寿和抗压能力的调节

基本信息

批准号：
10688324
负责人：
Eric Lieberman Greer
金额：
--
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10688324
关键词：
Adenosine Age Aging Animals Binding Biochemical Biological Caenorhabditis elegans Cells Complex Coupled Cues DNA Methylation Data Enzymes Eukaryota Event Genetic Genetic Translation Goals Health Heat-Shock Response Heterogeneity High Pressure Liquid Chromatography In Vitro Individual Lead Longevity Maintenance Mass Spectrum Analysis Messenger RNA Metabolism Methods Methylation Methyltransferase Modification Molecular Mus Organism Outcome Pathway interactions Play Process Protein Biosynthesis Proteins Proteome RNA interference screen RNA methylation RNA, Ribosomal, 18S Regulation Resistance Ribosomal DNA Ribosomal Proteins Ribosomal RNA Ribosomes Role Signal Pathway Specific qualifier value Specificity Stimulus Stress Structure Testing Tissues Transcript Transgenic Organisms Translating Translations Work biological adaptation to stress environmental stressor experimental study gene product healthy aging in vivo insight mutant polysome profiling preservation response ribosome profiling transcriptome ultraviolet irradiation

项目摘要

Project Summary The goal of this project is to understand how ribosomal RNA methylation can regulate translation of specific proteins to regulate aging. Disruption of the proteome is a hallmark of aging. Having the capacity to express the appropriate protein in response to environmental cues is an essential and evolutionarily conserved process. Therefore, preserving the proteome is critical for maintaining organismal health and healthy aging. However, how aging-responsive mRNAs are selectively translated is unknown. We recently identified that ribosomal RNA methylation could facilitate the translation of a specific subset of proteins. Additionally, we characterized how ribosome occupancy changes as an organism ages and determined that changes in ribosomal DNA methylation are sufficient to project the organismal age. Whether ribosomal RNA methylation plays a role in preserving proteome integrity as organisms age is still unclear. We have recently found that enzymes which regulate RNA methylation and RNA methylation itself are dysregulated during aging and in response to stress. We found that an N6-adenosine methyltransferase, METL-5, directly methylates adenosine 1717 on 18S ribosomal RNA in C. elegans. Methylation of adenosine 1717 enhances ribosomal binding and selective translation of specific mRNAs. Our preliminary data shows that metl-5 deficient animals grow normally under homeostatic conditions; however, metl-5 mutants are resistant to a variety of stresses, including heat shock and UV irradiation. Thus, methylation of a specific residue of 18S rRNA by METL-5 selectively enhances translation of specific transcripts to regulate stress resistance. However, whether rRNA methylation more broadly can regulate age and stress-responsive translation and whether this dysregulation drives the aging process is still unknown. By performing a directed RNAi screen, we identified additional rRNA methyltransferases that when deleted increase C. elegans lifespan. These preliminary findings suggest that ribosomal RNA methylation can facilitate selective translation of specific transcripts providing another layer of regulation of the stress response and aging. Capitalizing on this preliminary data we will use genetic, biochemical, and molecular approaches both in vitro and in vivo to dissect the role of rRNA methylation in regulating aging and stress resistance. Our underlying hypothesis is that rRNA methylation promotes ribosome heterogeneity in response to stress conditions and aging to facilitate the appropriate translation of stress resistance transcripts.

项目概要该项目的目标是了解核糖体 RNA 甲基化如何调节特定的翻译调节衰老的蛋白质。蛋白质组的破坏是衰老的标志。有表达能力响应环境线索的适当蛋白质是一种必需的且进化上保守的蛋白质过程。因此，保存蛋白质组对于维持机体健康和健康衰老至关重要。然而，衰老反应性 mRNA 如何选择性翻译尚不清楚。我们最近发现核糖体 RNA 甲基化可以促进特定蛋白质子集的翻译。此外，我们描述了核糖体占据如何随着生物体老化而变化，并确定了核糖体 DNA 甲基化足以预测生物体年龄。核糖体RNA是否甲基化随着生物体年龄的增长，其在保持蛋白质组完整性方面所发挥的作用仍不清楚。我们最近发现调节 RNA 甲基化的酶和 RNA 甲基化本身在衰老和衰老过程中失调。对压力的反应。我们发现 N6-腺苷甲基转移酶 METL-5 直接甲基化腺苷第1717章线虫中的18S核糖体RNA。 1717 腺苷甲基化增强核糖体结合选择性翻译特定 mRNA。我们的初步数据表明，metl-5 缺陷的动物生长通常在稳态条件下；然而，metl-5突变体能够抵抗多种压力，包括热激和紫外线照射。因此，METL-5 对 18S rRNA 的特定残基进行甲基化选择性增强特定转录本的翻译以调节应激抵抗力。然而，rRNA是否更广泛地，甲基化可以调节年龄和应激反应性翻译，以及这种失调是否驱动衰老过程的因素仍然未知。通过进行定向 RNAi 筛选，我们鉴定了额外的 rRNA 甲基转移酶被删除后会增加秀丽隐杆线虫的寿命。这些初步发现表明核糖体 RNA 甲基化可以促进特定转录本的选择性翻译，提供另一层应激反应和衰老的调节。利用这些初步数据，我们将使用遗传、体外和体内的生物化学和分子方法来剖析 rRNA 甲基化在调节衰老和抗应激能力。我们的基本假设是 rRNA 甲基化促进核糖体对压力条件和衰老的反应异质性，以促进压力的适当转化抵抗记录。