Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway
| Autor: | Xavier Deschênes-Simard, Marlene Oeffinger, Cornelia E. Zorca, Sebastian Igelmann, Léa Brakier-Gingras, Daniel Zenklusen, Emmanuelle Saint-Germain, Olga Moiseeva, Geneviève Huot, Neylen Del Toro, Lian Mignacca, Benjamin Le Calvé, Marinieve Montero, Marie-Camille Rowell, Frédéric Lessard, Véronique Bourdeau, Gerardo Ferbeyre, Christian Trahan, Marina Bury, Stéphane Lopes-Paciencia |
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| Rok vydání: | 2018 |
| Předmět: |
Ribosomal Proteins
0301 basic medicine Senescence Time Factors Cell cycle checkpoint Nucleolus Ribosome biogenesis Retinoblastoma Protein 03 medical and health sciences Ribosomal protein Neoplasms RNA Precursors Humans Phosphorylation Cellular Senescence Gene knockdown Chemistry HEK 293 cells Cyclin-Dependent Kinase 4 RNA-Binding Proteins Cell Cycle Checkpoints Cell Biology Blood Coagulation Factors Cell biology HEK293 Cells 030104 developmental biology RNA Ribosomal PC-3 Cells Signal transduction Ribosomes Protein Binding Signal Transduction |
| Zdroj: | Nature Cell Biology. 20:789-799 |
| ISSN: | 1476-4679 1465-7392 |
| DOI: | 10.1038/s41556-018-0127-y |
| Popis: | Cellular senescence is a tumour suppressor programme characterized by a stable cell cycle arrest. Here we report that cellular senescence triggered by a variety of stimuli leads to diminished ribosome biogenesis and the accumulation of both rRNA precursors and ribosomal proteins. These defects were associated with reduced expression of several ribosome biogenesis factors, the knockdown of which was also sufficient to induce senescence. Genetic analysis revealed that Rb but not p53 was required for the senescence response to altered ribosome biogenesis. Mechanistically, the ribosomal protein S14 (RPS14 or uS11) accumulates in the soluble non-ribosomal fraction of senescent cells, where it binds and inhibits CDK4 (cyclin-dependent kinase 4). Overexpression of RPS14 is sufficient to inhibit Rb phosphorylation, inducing cell cycle arrest and senescence. Here we describe a mechanism for maintaining the senescent cell cycle arrest that may be relevant for cancer therapy, as well as biomarkers to identify senescent cells. |
| Databáze: | OpenAIRE |
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