Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway

Frédéric Lessard, Sebastian Igelmann, Christian Trahan, Geneviève Huot, Emmanuelle Saint-Germain, Lian Mignacca, Neylen Del Toro, Stéphane Lopes-Paciencia, Benjamin Le Calve, Marinieve Montero, Xavier Deschënes-Simard, Marina Bury, Olga Moiseeva, Marie-Camille Rowell, Marlene Oeffinger, Cornelia E. Zorca, Daniel Zenklusen, Léa Brakier-Gingras, Véronique Bourdeau, Gerardo Ferbeyre

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Résumé

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.

langue originaleAnglais
Pages (de - à)789-799
Nombre de pages11
journalnature cell biology
Volume20
Numéro de publication7
Les DOIs
Etat de la publicationPublié - 1 juil. 2018

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