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

• 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
• 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

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 这个项目的目标是了解核糖体RNA甲基化如何调节特定基因的翻译 调节衰老的蛋白质。蛋白质组的破坏是衰老的一个标志。有表达能力的 适当的蛋白质对环境信号的反应是必不可少的，在进化上是保守的 进程。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，对衰老有反应的mRNAs是如何选择性翻译的尚不清楚。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 描述了核糖体占有率如何随着生物体年龄的变化而变化，并确定了核糖体在 核糖体DNA甲基化足以推测生物年龄。核糖体RNA甲基化是否 在生物体年龄尚不清楚的情况下，在保持蛋白质组完整性方面发挥作用。我们最近发现， 调节RNA甲基化和RNA甲基化本身的酶在衰老过程中和在 对压力的反应。我们发现，一种N6-腺苷甲基转移酶，METL-5，直接甲基化腺苷 1717在线虫18S核糖体RNA上。腺苷1717甲基化增强核糖体结合和 选择性翻译特定的mRNAs。我们的初步数据显示，缺乏metl-5的动物 通常在动态平衡条件下；然而，metl-5突变体对各种胁迫具有抗性， 包括热休克和紫外线照射。我们还有初步数据表明，N6-二甲基二甲基的缺失 腺苷(m6，2a)甲基转移酶，DIMT-1，使18S rRNA上的腺苷1735和1736甲基化 调节特定mRNAs的选择性核糖体结合和翻译，并导致延长寿命和 抗逆性。因此，METL-5或DIMT-1选择性地甲基化18S rRNA的特定残基 增强特定转录本的翻译，以调节抗逆性和寿命。然而，无论是 更广泛地说，rRNA甲基化可以调节年龄和应激反应翻译，以及这种失调是如何 驾驶的老化过程仍不得而知。我们的初步发现表明，核糖体RNA甲基化可以 促进特定转录本的选择性翻译，为应激反应提供另一层调节 和衰老。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，剖析rRNA甲基化在调节衰老和应激抵抗中的作用。我们的 潜在的假说是rRNA甲基化促进了核糖体在应激反应中的异质性 条件和老化，以促进逆境抗性转录本的适当翻译。