Center for Proteomics and Molecular Therapeutics and Biochemistry and Molecular Biology, Chicago Medical School, Rosalind Franklin University of Medicine & Science, North Chicago, IL, 60064, USA.
Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Histochem Cell Biol. 2024 Jul;162(1-2):161-183. doi: 10.1007/s00418-024-02297-7. Epub 2024 May 17.
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.
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，核糖体是合成细胞所需的所有蛋白质的必需的大分子机器。核糖体的组装在进化上是保守的，占细胞生长、增殖和维持平衡所需的最耗能的细胞过程。尽管这一过程意义重大，但核仁在核糖体生物发生中的亚结构机制原则直到最近才开始显现。在这里，我们使用先进的超分辨率显微镜和单分子 MINFLUX 纳米显微镜，提供了一个新的视角，研究了控制核糖体 RNA 种子核仁形成的机制原则，以及由此产生的核仁的三分体亚组织，部分是由液-液相分离驱动的。随着冷冻电子显微镜（cryoEM）对核糖体生物发生中间体的结构分析的最新进展，我们强调了目前对核仁中前核糖体亚基逐步组装的理解。最后，我们讨论了新型抗癌药物候选物如何靶向核糖体生物发生的早期步骤，以利用这些对生长抑制和肿瘤控制至关重要的依赖性。
