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Ribosome biogenesis plays a pivotal role in maintaining stem cell homeostasis, yet the precise regulatory mechanisms governing this process in mouse embryonic stem cells (mESCs) remain largely unknown. In this investigation, we ascertain that DEAD-box RNA helicase 10 (DDX10) is indispensable for upholding cellular homeostasis and the viability of mESCs. Positioned predominantly at the nucleolar dense fibrillar component (DFC) and granular component (GC), DDX10 predominantly binds to 45S ribosomal RNA (rRNA) and orchestrates ribosome biogenesis. Degradation of DDX10 prevents the release of U3 snoRNA from pre-rRNA, leading to perturbed pre-rRNA processing and compromised maturation of the 18S rRNA, thereby disrupting the biogenesis of the small ribosomal subunit. Moreover, DDX10 participates in the process of liquid-liquid phase separation (LLPS), which is necessary for efficient ribosome biogenesis. Notably, the NUP98-DDX10 fusion associated with acute myelocytic leukemia (AML) alters the cellular localization of DDX10 and results in loss of ability to regulate pre-rRNA processing. Collectively, this study reveals the critical role of DDX10 as a pivotal regulator of ribosome biogenesis in mESCs.

核糖体生物发生（Ribosome biogenesis）在维持干细胞稳态（stem cell homeostasis）过程中发挥关键作用，然而调控小鼠胚胎干细胞（mouse embryonic stem cells, mESCs）中该过程的精确分子机制仍在很大程度上尚不明确。本研究中，我们证实DEAD盒RNA解旋酶10（DEAD-box RNA helicase 10, DDX10）对于维持细胞稳态以及保障小鼠胚胎干细胞的存活至关重要。DDX10主要定位于核仁致密纤维组分（nucleolar dense fibrillar component, DFC）与颗粒组分（granular component, GC），可结合45S核糖体RNA（45S ribosomal RNA, rRNA）并调控核糖体生物发生过程。降解DDX10会阻碍U3小核仁RNA（U3 snoRNA）从前体核糖体RNA（pre-rRNA）上的释放，进而导致前体核糖体RNA加工紊乱、18S核糖体RNA（18S rRNA）成熟受损，最终破坏核糖体小亚基（small ribosomal subunit）的生物发生。此外，DDX10参与液液相分离（liquid-liquid phase separation, LLPS）过程，而该过程对于高效的核糖体生物发生不可或缺。值得注意的是，与急性髓系白血病（acute myelocytic leukemia, AML）相关的NUP98-DDX10融合蛋白会改变DDX10的细胞定位，并使其丧失调控前体核糖体RNA加工的能力。综上，本研究揭示了DDX10作为小鼠胚胎干细胞中核糖体生物发生关键调控因子的重要作用。