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Generation and Isolation of Cell Cycle-arrested Cells with Complex Karyotypes
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Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway

Frédéric Lessard1, Sebastian Igelmann1, Christian Trahan2

  • 1Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, Quebec, Canada.

Nature Cell Biology
|June 27, 2018
PubMed

Insights

Cellular senescence, a key tumor suppressor mechanism, involves impaired ribosome production. Accumulation of ribosomal protein S14 (RPS14) inhibits CDK4, maintaining cell cycle arrest and offering potential cancer therapy targets.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Cellular senescence is a crucial tumor suppressor mechanism characterized by stable cell cycle arrest.
  • Senescence can be induced by various cellular stresses.

Purpose of the Study:

  • To investigate the role of ribosome biogenesis in cellular senescence.
  • To identify mechanisms maintaining the senescent cell cycle arrest.
  • To explore potential therapeutic targets and biomarkers for senescent cells.

Main Methods:

  • Induction of cellular senescence via diverse stimuli.
  • Analysis of ribosome biogenesis, rRNA precursors, and ribosomal protein levels.
  • Knockdown experiments for ribosome biogenesis factors.
  • Genetic analysis involving Rb and p53.
  • Investigation of ribosomal protein S14 (RPS14) interactions with CDK4.

Main Results:

  • Cellular senescence leads to reduced ribosome biogenesis and accumulation of rRNA precursors and ribosomal proteins.
  • Reduced expression of ribosome biogenesis factors induces senescence.
  • The retinoblastoma protein (Rb), but not p53, is essential for the senescence response to impaired ribosome biogenesis.
  • Accumulated RPS14 binds and inhibits cyclin-dependent kinase 4 (CDK4), preventing Rb phosphorylation and inducing cell cycle arrest.

Conclusions:

  • Impaired ribosome biogenesis is a hallmark of cellular senescence.
  • RPS14-mediated inhibition of CDK4 is a key mechanism for maintaining senescent cell cycle arrest.
  • This pathway presents potential targets for cancer therapy and biomarkers for senescent cells.

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