Perturbation of Ribosome Biogenesis Drives Cells into Senescence through 5S RNP-Mediated p53 Activation

The 5S ribonucleoprotein particle (RNP) complex, consisting of RPL11, RPL5, and 5S rRNA, is implicated in p53 regulation under ribotoxic stress. Here, we show that the 5S RNP contributes to p53 activation and promotes cellular senescence in response to oncogenic or replicative stress. Oncogenic stress accelerates rRNA transcription and replicative stress delays rRNA processing, resulting in RPL11 and RPL5 accumulation in the ribosome-free fraction, where they bind MDM2. Experimental upregulation of rRNA transcription or downregulation of rRNA processing, mimicking the nucleolus under oncogenic or replicative stress, respectively, also induces RPL11-mediated p53 activation and cellular senescence. We demonstrate that exogenous expression of certain rRNA-processing factors rescues the processing defect, attenuates p53 accumulation, and increases replicative lifespan. To summarize, the nucleolar-5S RNP-p53 pathway functions as a senescence inducer in response to oncogenic and replicative stresses. [Display omitted] •Oncogenic stress enhances rRNA transcription, inducing p53 activation and senescence•Replicative stress delays rRNA processing, inducing p53 activation and senescence•5S RNP is required for p53 activation and senescence under these stresses•Exogenous expression of rRNA-processing factors extends the replicative lifespan Somatic cells stop growing after repeated passage in a culture or oncogene activation, a state termed senescence. Nishimura et al. reveal that the nucleolus acts as a key regulator of senescence. Senescence was delayed by controlling ribosome biogenesis, providing a link between nucleolar function and the induction of senescence.