Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway
2018
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.
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