The molecular mechanism of pre-mRNA splicing

pre-mRNA剪接的分子机制

• 批准号: 10624937
• 负责人: RUI ZHAO
• 金额: $ 82.56万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624937
• 关键词: Biochemical; Complex; Coupling; Disease; Essential Genes; Esterification; Eukaryota; Exons; Gene Expression; Genetic; Genetic Diseases; Genetic Transcription; Genomic approach; Goals; Introns; Knowledge; Molecular; Proteins; RNA; RNA Splicing; Reaction; Small Nuclear Ribonucleoproteins; Spliceosomes; human disease; mRNA Precursor; protein complex

Summary Pre-mRNA splicing is essential for gene expression in all eukaryotes and errors in splicing cause genetic disorders and many other diseases. A thorough understanding of the molecular mechanisms of pre-mRNA splicing has the potential to provide useful approaches for human disease therapy. The splicing of introns is carried out through two transesterification reactions catalyzed by the spliceosome, a large RNA/protein complex composed of five snRNPs (U1, U2, U4, U5, U6) and many non-snRNP related protein factors. The spliceosome undergoes dramatic changes in a splicing cycle, generating the E, A, Pre-B, B, Bact, B*, C, C*, P, and ILS complexes. Genetic, biochemical, and structural studies in the past four decades have generated tremendous information on the mechanism of splicing, but significant knowledge gaps remain. Our goal in the next 5 years is to use a combination of structural, biochemical, and genetic/genomics approaches to understand the mechanism and modulation of alternative 5’ ss recognition, the mechanism of exon definition, and the mechanism and function of transcription and splicing coupling. We envision that these projects will fill several significant knowledge gaps and advance our understanding of the mechanism of splicing.

总结 前体mRNA剪接对于所有真核生物中的基因表达是必不可少的，并且剪接中的错误导致遗传性疾病。 疾病和许多其他疾病。对前mRNA分子机制的深入了解 剪接具有为人类疾病治疗提供有用方法的潜力。内含子的剪接是 通过剪接体催化的两个酯交换反应进行，剪接体是一种大的RNA/蛋白质， 由5个snRNP（U1、U2、U4、U 5、U6）和许多非snRNP相关蛋白因子组成的复合物。的 剪接体在剪接循环中经历显著变化，产生E、A、前B、B、Bact、B*、C、C*、P， 和ILS复合体。在过去的四十年里，遗传、生物化学和结构研究产生了 关于剪接机制的大量信息，但仍然存在重大的知识差距。我们的目标是 未来5年将结合使用结构、生化和遗传/基因组学方法， 理解选择性5' ss识别的机制和调节，外显子定义的机制， 以及转录和剪接偶联的机制和功能。我们预计，这些项目将填补 几个重要的知识空白，并推进我们对剪接机制的理解。

项目成果

Selected humanization of yeast U1 snRNP leads to global suppression of pre-mRNA splicing and mitochondrial dysfunction in the budding yeast.

酵母 U1 snRNP 的选择性人源化导致芽殖酵母中前 mRNA 剪接和线粒体功能障碍的整体抑制。

• DOI: 10.1101/2023.12.15.571893
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Chalivendra,Subbaiah;Shi,Shasha;Li,Xueni;Kuang,Zhiling;Giovinazzo,Joseph;Zhang,Lingdi;Rossi,John;Saviola,AnthonyJ;Wang,Jingxin;Welty,Robb;Liu,Shiheng;Vaeth,Katherine;Zhou,ZHong;Hansen,KirkC;Taliaferro,JMatthew;Zhao,Rui
• 通讯作者: Zhao,Rui