Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Remix Therapeutics, Watertown, MA, USA.
Science. 2024 Nov;386(6721):551-560. doi: 10.1126/science.adn8105. Epub 2024 Oct 31.
The spliceosome is the complex molecular machinery that sequentially assembles on eukaryotic messenger RNA precursors to remove introns (pre-mRNA splicing), a physiologically regulated process altered in numerous pathologies. We report transcriptome-wide analyses upon systematic knock down of 305 spliceosome components and regulators in human cancer cells and the reconstruction of functional splicing factor networks that govern different classes of alternative splicing decisions. The results disentangle intricate circuits of splicing factor cross-regulation, reveal that the precise architecture of late-assembling U4/U6.U5 tri-small nuclear ribonucleoprotein (snRNP) complexes regulates splice site pairing, and discover an unprecedented division of labor among protein components of U1 snRNP for regulating exon definition and alternative 5' splice site selection. Thus, we provide a resource to explore physiological and pathological mechanisms of splicing regulation.
剪接体是一种复杂的分子机器，它在真核信使 RNA 前体上依次组装，以去除内含子（pre-mRNA 剪接），这是一个在许多病理情况下发生改变的生理调节过程。我们报告了在人类癌细胞中系统敲低 305 个剪接体成分和调节剂后进行的全转录组分析，并重建了控制不同类别选择性剪接决定的功能剪接因子网络。研究结果揭示了剪接因子交叉调控的复杂回路，表明晚期组装的 U4/U6.U5 三小核核糖核蛋白（snRNP）复合物的精确结构调节剪接位点配对，并发现 U1 snRNP 的蛋白质成分在调节外显子定义和选择性 5' 剪接位点选择方面存在前所未有的分工。因此，我们提供了一种资源来探索剪接调控的生理和病理机制。
