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 Messenger RNA剪接是由大型大分子机器（剪接体）进行的 当它组装到预选赛前RNA上时，它会经历戏剧性的重排。我们的 了解这种优雅的核糖核蛋白机的理解已大大提高 冷冻结构的可用性和拼接组件的广泛“零件清单”。但是，很多 关于剪接组装如何发生在剪接体中的剪接组件如何进行的问题 机械组装到新生的转录本上，该转录本正在从染色质中积极转录 模板，即共转录。此外，剪接体和剪接催化的组装是 在内含子保留的真核生物中，受到严格的调节，实际上存在宽度的例子。 但是，这种现象的调节后果仍然晦涩难懂。在强者的指导下 初步数据，我们探讨了这两个杰出的挑战，并解决以下 问题：（1）染色质如何影响剪接体组装，反之亦然，即如何 共转录剪接体组装会影响染色质的状态？ （2）内含子如何 保留有助于基因调节？ （3）内含子积累的错误调节如何导致 细胞毒性和疾病？