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.

概括 mRNA 前体剪接对于所有真核生物的基因表达至关重要，剪接错误会导致遗传 全面了解前 mRNA 的分子机制。 剪接有可能为人类疾病治疗提供有用的方法。 通过剪接体（一种大的 RNA/蛋白质）催化的两个酯交换反应进行 由五个 snRNP（U1、U2、U4、U5、U6）和许多非 snRNP 相关蛋白因子组成的复合物。 剪接体在剪接周期中经历巨大的变化，产生E、A、Pre-B、B、Bact、B*、C、C*、P、 和 ILS 复合物在过去四十年中已经产生。 关于剪接机制的大量信息，但仍然存在重大知识差距。 未来 5 年将结合使用结构、生化和遗传/基因组学方法 了解替代5’ss识别的机制和调制，外显子定义的机制， 我们预计这些项目将填补转录和剪接耦合的机制和功能。 几个重要的知识差距并促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。

• 发表时间: 2023-12-15
• 作者: Chalivendra, Subbaiah;Shi, Shasha;Li, Xueni;Kuang, Zhiling;Giovinazzo, Joseph;Zhang, Lingdi;Rossi, John;Saviola, Anthony J;Wang, Jingxin;Welty, Robb;Liu, Shiheng;Vaeth, Katherine;Zhou, Z Hong;Hansen, Kirk C;Taliaferro, J Matthew;Zhao, Rui
• 通讯作者: Zhao, Rui