Nuclear RNA homeostasis promotes systems-level coordination of cell fate and senescence

Understanding cellular coordination remains a challenge despite knowledge of individual pathways. The RNA exosome, targeting a wide range of RNA substrates, is often downregulated in cellular senescence. Utilizing an auxin-inducible system, we observed that RNA exosome depletion in embryonic stem cells significantly affects the transcriptome and proteome, causing pluripotency loss and pre-senescence onset. Mechanistically, exosome depletion triggers acute nuclear RNA aggregation, disrupting nuclear RNA-protein equilibrium. This disturbance limits nuclear protein availability and hinders polymerase initiation and engagement, reducing gene transcription. Concurrently, it promptly disrupts nucleolar transcription, ribosomal processes, and nuclear exporting, resulting in a translational shutdown. Prolonged exosome depletion induces nuclear structural changes resembling senescent cells, including aberrant chromatin compaction, chromocenter disassembly, and intensified heterochromatic foci. These effects suggest that the dynamic turnover of nuclear RNA orchestrates crosstalk between essential processes to optimize cellular function. Disruptions in nuclear RNA homeostasis result in systemic functional decline, altering the cell state and promoting senescence. [Display omitted] •The RNA exosome governs nuclear ribosomal, messenger, and noncoding RNA homeostasis•Dynamic RNA turnover orchestrates nuclear organization and processes•RNA exosome depletion induces nuclear RNA aggregation, impeding transcription•Prolonged depletion disrupts chromatin state and translation, eliciting pre-senescence Han et al. report that the RNA exosome complex regulates nuclear RNA homeostasis, synchronizing rRNA and mRNA transcription with translation and facilitating chromatin organization. This RNA-mediated systematic coordination is vital for cellular identity and fitness, with a critical impact on preventing senescence.