Regulation of Ribosome Biogenesis

核糖体生物发生的调控

• 批准号: 10707447
• 负责人: Shawn M Lyons
• 金额: $ 41.25万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707447
• 关键词: Address; Affect; Biogenesis; Cell Nucleolus; Complex; Development; Disease; Event; Genes; Genetic Processes; Genetic Transcription; Genome; Heterogeneity; Human; Light; Molecular; Nuclear; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Process; Production; Proteins; RNA Processing; Regulation; Ribosomal Proteins; Ribosomal RNA; Ribosomes; Signal Pathway; Site; Stimulus; Stress; Techniques; Therapeutic; Time; Transcription Process; Variant; Virus Diseases; Work; biological adaptation to stress; differential expression; genetic information; molecular subtypes; multiple omics; novel; posttranscriptional; rRNA Genes; targeted treatment

Abstract Ribosomes are among the most ancient, intricate, and essential cellular machines whose function is to process genetic information to generate cellular proteins. Human ribosomes are incredibly complex, consisting of 80 ribosomal proteins and four heavily modified ribosomal RNAs (rRNA), which must be precisely assembled. Further, the largest pre-rRNA is transcribed from a polycistronic gene repeated more than 300 times in the genome. This pre-rRNA must be post-transcriptionally processed to remove external and internal spacers to release mature rRNAs. The majority of these assembly events occur in a specialized nuclear body called the nucleolus. Owing, in part, to their complex assembly process, it is now appreciated that not all ribosomes are the same, and it has been suggested that heterogenous ribosomes may have specialized functions. We have discovered that an undetermined stress response pathway regulates early events in rRNA processing. We have shown that this pathway is activated by oxidative stress, select viral infections, and chemotherapeutic drugs. Activation results in unprocessed pre-rRNA being stored in the nucleolus, which re-enters the maturation process when stress resolves. We are undertaking a multi-omics approach to uncover this pathway and determine how this prolonged stalling of processing and storage of pre-rRNA in the nucleolus affects the assembly and activity of ribosomes generated in this time window. We have developed a novel technique that allows for the time- resolved capture of ribosomes to address this question. Further, analysis of processing sites demonstrates profound sequence heterogeneity across the different repeated genes through the genome, raising the possibility that processing events are differentially regulated between rRNA genes. We expect to clarify the sequence motifs required for early rRNA processing and determine how naturally occurring variants contribute to the differential expression of sub-types of ribosomes. We seek to understand better the basic principles governing ribosome biogenesis in light of diverse sequence variation and how various stimuli alter the process of ribosome assembly.

摘要 核糖体是最古老、最复杂和最基本的细胞机器之一，其功能是处理 遗传信息来产生细胞蛋白质。人类的核糖体非常复杂，由80个 核糖体蛋白和四个高度修饰的核糖体RNA（rRNA），它们必须精确组装。 此外，最大的前体rRNA是从多顺反子基因转录的，该基因在DNA中重复超过300次。 基因组这种前rRNA必须经过转录后处理，以去除外部和内部间隔区， 释放成熟的rRNA。大多数这些组装事件发生在一个专门的核机构称为 核仁部分地由于它们复杂的组装过程，现在认识到并非所有的核糖体都是核糖体。 同样，有人认为，异质核糖体可能具有特殊的功能。我们有 发现了一个未确定的应激反应途径调节rRNA加工的早期事件。我们有 显示该途径被氧化应激、选择性病毒感染和化疗药物激活。 激活导致未加工的前rRNA储存在核仁中，重新进入成熟过程 当压力消除。我们正在采取多组学方法来揭示这一途径，并确定如何 这种前体rRNA在核仁中加工和储存的长期停滞影响了RNA的组装和活性， 在这个时间窗内产生的核糖体。我们发明了一种新技术可以让时间- 解决了核糖体的捕获来解决这个问题。此外，对加工地点的分析表明， 基因组中不同重复基因的序列异质性， 加工事件在rRNA基因之间受到不同的调节。我们希望能澄清序列基序 并确定天然存在的变体如何有助于早期rRNA加工的差异。 核糖体亚型的表达。我们试图更好地理解核糖体的基本原理 生物起源的光不同的序列变异和各种刺激如何改变核糖体组装的过程。