Liu Yuan, He Shiyang, Pyo Kawon, Franklin Reuben, Maaz Ibrahim B, Cai Chen, Shah Kriti, Cheloufi Sihem, Marzluff William F, Murn Jernej
Department of Biochemistry, University of California, Riverside, 3401 Watkins Drive, Boyce Hall, Riverside, CA, USA.
Center for RNA Biology and Medicine, 900 University Ave, Riverside, CA, USA.
Nat Commun. 2025 Jun 18;16(1):5342. doi: 10.1038/s41467-025-60471-4.
Cellular quiescence is a state of reversible proliferative arrest that plays essential roles in development, resistance to stress, aging, and longevity of organisms. Here we report that rapid depletion of RNase MRP, a deeply conserved RNA-based enzyme required for rRNA biosynthesis, induces a long-term yet reversible proliferative arrest in human cells. Severely compromised biogenesis of rRNAs along with acute transcriptional reprogramming precede a gradual decline of the critical cellular functions. Unexpectedly, many arresting cells show increased levels of histone mRNAs, which accumulate locally in the cytoplasm, and S-phase DNA amount. The ensuing proliferative arrest is entered from multiple stages of the cell cycle and can last for several weeks with uncompromised cell viability. Strikingly, restoring expression of RNase MRP leads to a complete reversal of the arrested state with resumed cell proliferation at the speed of control cells. We suggest that targeting rRNA biogenesis may provide a general strategy for rapid induction of a reversible proliferative arrest, with implications for understanding and manipulating cellular quiescence.
细胞静止是一种可逆的增殖停滞状态，在生物体的发育、应激抵抗、衰老和长寿中发挥着重要作用。在此，我们报告核糖核酸酶MRP（rRNA生物合成所需的一种高度保守的核糖核酸酶）的快速耗竭会在人类细胞中诱导长期但可逆的增殖停滞。rRNA生物合成严重受损以及急性转录重编程先于关键细胞功能的逐渐衰退。出乎意料的是，许多停滞的细胞显示组蛋白mRNA水平升高，其在细胞质中局部积累，以及S期DNA量增加。随后的增殖停滞从细胞周期的多个阶段进入，并且可以持续数周，细胞活力不受影响。引人注目的是，恢复核糖核酸酶MRP的表达会导致停滞状态完全逆转，细胞以对照细胞的速度恢复增殖。我们认为，靶向rRNA生物合成可能为快速诱导可逆的增殖停滞提供一种通用策略，这对理解和操纵细胞静止具有重要意义。
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