Senescence-associated Ribosome Biogenesis Defects Contributes to Cell Cycle Arrest Through the Rb Pathway

Nat Cell Biol. 2018 Jul;20(7):789-799. doi: 10.1038/s41556-018-0127-y. Epub 2018 Jun 25.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Coagulation Factors / genetics
  • Blood Coagulation Factors / metabolism
  • Cell Cycle Checkpoints*
  • Cellular Senescence*
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / metabolism
  • HEK293 Cells
  • Humans
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • PC-3 Cells
  • Phosphorylation
  • Protein Binding
  • RNA Precursors / biosynthesis
  • RNA Precursors / genetics
  • RNA, Ribosomal / biosynthesis
  • RNA, Ribosomal / genetics
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism*
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism
  • Ribosomes / genetics
  • Ribosomes / metabolism*
  • Signal Transduction
  • Time Factors

Substances

  • Blood Coagulation Factors
  • RNA Precursors
  • RNA, Ribosomal
  • RPL29 protein, human
  • RPS14 protein, human
  • Retinoblastoma Protein
  • Ribosomal Proteins
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4