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

Cellular senescenceis a tumour suppressor programme characterized by a stable cell cyclearrest. Here we report that cellular senescencetriggered by a variety of stimuli leads to diminished ribosome biogenesisand the accumulation of both rRNA precursors and ribosomal proteins. These defects were associated with reduced expression of several ribosome biogenesisfactors, the knockdown of which was also sufficient to induce senescence. Genetic analysisrevealed that Rb but not p53 was required for the senescenceresponse to altered ribosome biogenesis. Mechanistically, the ribosomal proteinS14 (RPS14 or uS11) accumulates in the soluble non- ribosomalfraction of senescentcells, where it binds and inhibits CDK4 ( cyclin-dependent kinase 4). Overexpression of RPS14 is sufficient to inhibit Rb phosphorylation, inducing cell cyclearrest and senescence. Here we describe a mechanism for maintaining the senescent cell cyclearrest that may be relevant for cancer therapy, as well as biomarkers to identify senescentcells.