DEAD-box RNA helicase 10 is required for 18S rRNA maturation by controlling the release of U3 snoRNA from pre-rRNA in embryonic stem cells

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 and granular component, 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 also 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) hampers the cellular localization of DDX10 and disrupts pre-rRNA processing. Collectively, this study reveals the critical role of DDX10 as a pivotal regulator of ribosome biogenesis in mESCs.

核糖体生物发生在维持干细胞稳态中发挥关键作用，然而调控小鼠胚胎干细胞（mESCs）中该过程的精确分子机制仍尚未完全阐明。本研究证实，DEAD盒RNA解旋酶10（DDX10）对于维持小鼠胚胎干细胞的细胞稳态与存活能力不可或缺。DDX10主要定位于核仁致密纤维组分与颗粒组分，主要结合45S核糖体RNA（rRNA）并调控核糖体生物发生过程。DDX10的降解会阻碍U3小核仁RNA（U3 snoRNA）从前体核糖体RNA（pre-rRNA）上的释放，导致前体核糖体RNA加工紊乱以及18S核糖体RNA（18S rRNA）成熟受损，进而破坏核糖体小亚基的生物发生。此外，DDX10还参与液液相分离（LLPS）过程，而该过程对于高效完成核糖体生物发生至关重要。值得注意的是，与急性髓系白血病（AML）相关的NUP98-DDX10融合蛋白会破坏DDX10的细胞定位，并扰乱前体核糖体RNA的加工过程。综上，本研究揭示了DDX10作为调控小鼠胚胎干细胞核糖体生物发生的关键调控因子的重要作用。