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

Abstract

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.

The Chromatin-Associated Phf12 Protein Maintains Nucleolar Integrity and Prevents Premature Cellular Senescence

“…Given the functional link between senescence and aging in mammals (41), it is tempting to speculate that Pf1 engages a program that coordinates nucleolar integrity and prevention of premature aging. In that aspect, it is intriguing to note the recent demonstration that perturbation of ribosomal biogenesis results in the activation of a senescence program in mammalian cells (42). It is also worth mentioning that the yeast Rpd3-Sin3 complex has been shown to catalyze histone H4 deacetylation at rDNA chromatin through this mechanism to control RNA polymerase I localization, rDNA transcription, and, as a consequence, the shape and size of the nucleolus in yeast cells (43).…”

Enhanced NOLC1 promotes cell senescence and represses hepatocellular carcinoma cell proliferation by disturbing the organization of nucleolus

“…The most well‐known function of the nucleolus is ribosome biogenesis, which includes pre‐rRNA transcription, processing, and mature rRNA assembly with ribosomal proteins. The stress on the nucleolus because of the abrogated rRNA synthesis could induce cell proliferation inhibition and cell senescence (Kazuho et al ., 2015). …”

The role of the nucleolus in neurodegeneration.

“…In cycling cells, such a condition is sufficient to produce hyper trophic nucleoli and induce the ribosomal stress response [187]. In addition to processing impairments, ribosomal stress associated hypertrophic nucleoli can also be triggered by oncogenic stimuli [187].…”

“…Nishimura et.al. (2015) showed that impairment of pre-rRNA processing can produce enlargement of the nucleolus and induce p53 through ribosomal proteins/MDM2 interactions [187]. Theoretically, inhibition of RNA Polymerase I and impairment of pre-rRNA processing should both produce stoichiometric errors in ribosomal components.…”

“…Oncogene Homolog (HRAS), was shown to stimulate the production of 47S pre-rRNA in excess of the cells capacity for processing [187]. Such a condition induced p53 mediated senescence and was rescued by overexpression of several processing proteins.…”