Reversible proliferative arrest induced by rapid depletion of RNase MRP

Yuan Liu, Shiyang He, Kawon Pyo, Reuben Franklin, Ibrahim B. Maaz, Chen Cai, Kriti Shah, Sihem Cheloufi (), William F. Marzluff () and Jernej Murn ()
Additional contact information
Yuan Liu: Boyce Hall
Shiyang He: Boyce Hall
Kawon Pyo: Boyce Hall
Reuben Franklin: Boyce Hall
Ibrahim B. Maaz: Boyce Hall
Chen Cai: Boyce Hall
Kriti Shah: Boyce Hall
Sihem Cheloufi: Boyce Hall
William F. Marzluff: University of North Carolina
Jernej Murn: Boyce Hall

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-60471-4

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