Mechanisms of messenger RNA splicing and RNA processing regulation

信使RNA剪接和RNA加工调控机制

• 批准号: 10623834
• 负责人: TRACY L JOHNSON
• 金额: $ 43.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-18 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623834
• 关键词: Address; Affect; Blindness; Catalysis; Cell physiology; Cells; Chromatin; Cryoelectron Microscopy; Data; Defect; Disease; Etiology; Eukaryota; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Interruption; Introns; Lead; Malignant Neoplasms; Messenger RNA; Molecular; Mutation; Nerve Degeneration; Process; RNA Processing; RNA Splicing; RNA, Messenger, Splicing; Reaction; Regulation; Ribonucleoproteins; Spliceosome Assembly Pathway; Spliceosomes; Stretching; Structure; Toxic effect; Transcript; Work; human disease; tool

PROJECT SUMMARY Messenger RNA splicing is carried out by a large macromolecular machine, the spliceosome, which undergoes dramatic rearrangements as it assembles onto a pre-messenger RNA. Our understanding of this elegant ribonucleoprotein machine has advanced significantly with the availability of cryoEM structures and an extensive “parts list” of splicing components. However, many questions remain about how spliceosome assembly takes place in the cell, where the spliceosome machinery assembles onto a nascent transcript that is being actively transcribed from a chromatin template, i.e. co-transcriptionally. Moreover, assembly of the spliceosome and splicing catalysis is tightly regulated and, in fact, there are widespread examples across eukaryotes of intron retention. Nonetheless, the regulatory consequences of this phenomenon remain obscure. Guided by strong preliminary data, we explore both of these outstanding challenges and address the following questions: (1) How does chromatin influence spliceosome assembly and vice versa, i.e. how does co-transcriptional spliceosome assembly affect the state of the chromatin? (2) How does intron retention contribute to gene regulation? (3) How does mis-regulation of intron accumulation lead to cellular toxicity and disease?

项目摘要 信使RNA剪接是由一个大的大分子机器，剪接体， 当它组装到前信使RNA上时会经历戏剧性的重排。我们 对这种优雅的核糖核蛋白机器的理解随着 cryoEM结构的可用性和拼接组件的广泛“零件清单”。但不少 关于剪接体如何在细胞中组装的问题仍然存在， 机器组装到一个新生的转录本上，该转录本正在从染色质活跃地转录 模板，即共转录。此外，剪接体的组装和剪接催化是 事实上，在真核生物中有广泛的内含子保留的例子。 尽管如此，这种现象的监管后果仍然不清楚。以强为导 根据初步数据，我们将探讨这两个突出的挑战，并解决以下问题 问题：（1）染色质如何影响剪接体组装，反之亦然，即如何 共转录剪接体组装影响染色质的状态？(2)内含子如何 保留有助于基因调控？(3)内含子积累的错误调节是如何导致 细胞毒性和疾病