Ribosomal RNA Methylation Regulation of Longevity and Stress Resistance

核糖体 RNA 甲基化对长寿和抗应激的调节

基本信息

批准号：
10781428
负责人：
Eric Lieberman Greer
金额：
$ 56.82万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10781428
关键词：
Acceleration Adenosine Affect Age Aging Animals Binding Biochemical Biological Caenorhabditis elegans Cells Complex Cues DNA Methylation Data Enzymes Eukaryota Event Genetic Goals Health Heat-Shock Response Heterogeneity Immunoprecipitation In Vitro Longevity Maintenance Messenger RNA Metabolism Methylation Methyltransferase Modification Molecular 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 Translational Regulation Translational Repression Translations Work biological adaptation to stress environmental stressor experimental study follow-up gene product healthy aging in vivo insight mRNA Translation 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. We also have preliminary data that deletion of an N6-dimethyl adenosine (m6,2A) methyltransferase, DIMT-1, which methylates adenosines 1735 and 1736 on 18S rRNA regulates selective ribosomal binding and translation of specific mRNAs and causes increased longevity and stress resistance. Thus, methylation of specific residues of the 18S rRNA by METL-5 or DIMT-1 selectively enhances translation of specific transcripts to regulate stress resistance and longevity. However, whether rRNA methylation more broadly can regulate age and stress-responsive translation and how this dysregulation drives the aging process is still unknown. Our 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.

项目摘要该项目的目的是了解核糖体RNA甲基化如何调节特定的翻译蛋白质调节衰老。蛋白质组的破坏是衰老的标志。有能力表达响应环境线索的适当蛋白质是必不可少的且进化保守的过程。因此，保留蛋白质组对于维持有机体健康和健康衰老至关重要。但是，如何选择性地翻译衰老响应性mRNA是未知的。我们最近确定核糖体RNA甲基化可以促进蛋白质特定子集的翻译。另外，我们表征了核糖体占用率如何随着生物体的年龄变化而确定的变化核糖体DNA甲基化足以投射有机年龄。核糖体RNA甲基化是否由于生物年龄仍然不清楚，因此在保持蛋白质组完整性方面起作用。我们最近发现调节RNA甲基化和RNA甲基化本身的酶在衰老期间和在对压力的反应。我们发现N6-腺苷甲基转移酶Metl-5直接甲基化腺苷 1717年在秀丽隐杆线虫中的18S核糖体RNA。腺苷1717的甲基化增强了核糖体结合和特定mRNA的选择性翻译。我们的初步数据表明，Metl-5不足动物生长通常在稳态条件下；但是，Met-5突变体对各种应力有抵抗力，包括热休克和紫外线照射。我们还拥有删除N6-二甲基的初步数据腺苷（M6,2A）甲基转移酶，DIMT-1，在18S rRNA上甲基化1735和1736 调节特定mRNA的选择性核糖体结合和翻译，并导致寿命增加和压力抗性。因此，通过Metl-5或DIMT-1选择性地对18S rRNA的特定残基的甲基化选择性地增强特定转录本的翻译以调节应力抗性和寿命。但是，是否 rRNA甲基化更广泛地调节年龄和应力响应性翻译以及这种失调如何驱动衰老过程仍然未知。我们的初步发现表明核糖体RNA甲基化可以促进对特定转录本的选择性翻译，从而提供另一层压力响应的调节和老化。利用这些初步数据，我们将使用遗传，生化和分子方法在体外和体内都可以剖析rRNA甲基化在调节衰老和抗压力抗性中的作用。我们的潜在的假设是rRNA甲基化促进应激的核糖体异质性条件和衰老，以促进应力抗性转录的适当翻译。