Perturbation of ribosome biogenesis drives cells into senescence through 5S RNP-mediated p53 activation

Cell Rep. 2015 Mar 3;10(8):1310-23. doi: 10.1016/j.celrep.2015.01.055. Epub 2015 Feb 26.

Abstract

The 5S ribonucleoprotein particle (RNP) complex, consisting of RPL11, RPL5, and 5S rRNA, is implicated in p53 regulation under ribotoxic stress. Here, we show that the 5S RNP contributes to p53 activation and promotes cellular senescence in response to oncogenic or replicative stress. Oncogenic stress accelerates rRNA transcription and replicative stress delays rRNA processing, resulting in RPL11 and RPL5 accumulation in the ribosome-free fraction, where they bind MDM2. Experimental upregulation of rRNA transcription or downregulation of rRNA processing, mimicking the nucleolus under oncogenic or replicative stress, respectively, also induces RPL11-mediated p53 activation and cellular senescence. We demonstrate that exogenous expression of certain rRNA-processing factors rescues the processing defect, attenuates p53 accumulation, and increases replicative lifespan. To summarize, the nucleolar-5S RNP-p53 pathway functions as a senescence inducer in response to oncogenic and replicative stresses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Nucleolus / metabolism
  • Cells, Cultured
  • Cellular Senescence*
  • Humans
  • MCF-7 Cells
  • Mice
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • RNA Interference
  • RNA, Ribosomal, 5S / metabolism
  • RNA, Small Interfering / metabolism
  • Ribosomal Proteins / antagonists & inhibitors
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism
  • Ribosomes / metabolism*
  • Transcriptional Activation
  • Tumor Suppressor Protein p53 / metabolism*
  • Up-Regulation

Substances

  • Cell Cycle Proteins
  • DKC1 protein, human
  • Nuclear Proteins
  • RNA, Ribosomal, 5S
  • RNA, Small Interfering
  • RRS1 protein, human
  • Ribosomal Proteins
  • Tumor Suppressor Protein p53
  • ribosomal protein L11
  • ribosomal protein L5, human
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2