Abstract：
The nucleolus is the largest membraneless organelle and nuclear body in mammalian cells. It is primarily involved in the biogenesis of ribosomes, essential macromolecular machines responsible for synthesizing all proteins required by the cell. The assembly of ribosomes is evolutionarily conserved and accounts for the most energy-consuming cellular process needed for cell growth, proliferation, and homeostasis. Despite the significance of this process, the substructural mechanistic principles of the nucleolar function in preribosome biogenesis have only recently begun to emerge. Here, we provide a new perspective using advanced super-resolution microscopy and single-molecule MINFLUX nanoscopy on the mechanistic principles governing ribosomal RNA-seeded nucleolar formation and the resulting tripartite suborganization of the nucleolus driven, in part, by liquid-liquid phase separation. With recent advances in the cryogenic electron microscopy (cryoEM) structural analysis of ribosome biogenesis intermediates, we highlight the current understanding of the step-wise assembly of preribosomal subunits in the nucleolus. Finally, we address how novel anticancer drug candidates target early steps in ribosome biogenesis to exploit these essential dependencies for growth arrest and tumor control.
摘要：
核仁是哺乳动物细胞中最大的无膜细胞器和核体。它主要参与核糖体的生物发生，负责合成细胞所需的所有蛋白质的必需大分子机器。核糖体的组装在进化上是保守的，并且是细胞生长所需的最消耗能量的细胞过程，扩散,和稳态。尽管这个过程很重要,前核糖体生物发生中核仁功能的亚结构机制原理直到最近才开始出现。这里,我们提供了一个新的观点，使用先进的超分辨率显微镜和单分子MINFLUX纳米镜对控制核糖体RNA种子的核仁形成的机制原理，在某种程度上,通过液-液相分离。随着核糖体生物合成中间体的低温电子显微镜（cryoEM）结构分析的最新进展，我们强调了目前对核仁前核糖体亚基逐步组装的理解.最后,我们探讨了新的抗癌药物候选物如何靶向核糖体生物发生的早期步骤，以利用这些基本依赖性来抑制生长和控制肿瘤。
