Perturbation of RNA Polymerase I transcription machinery by ablation of HEATR1 triggers the RPL5/RPL11-MDM2-p53 ribosome biogenesis stress checkpoint pathway in human cells

Cell Cycle. 2018;17(1):92-101. doi: 10.1080/15384101.2017.1403685. Epub 2017 Dec 10.

Abstract

Ribosome biogenesis is an energy consuming process which takes place mainly in the nucleolus. By producing ribosomes to fuel protein synthesis, it is tightly connected with cell growth and cell cycle control. Perturbation of ribosome biogenesis leads to the activation of p53 tumor suppressor protein promoting processes like cell cycle arrest, apoptosis or senescence. This ribosome biogenesis stress pathway activates p53 through sequestration of MDM2 by a subset of ribosomal proteins (RPs), thereby stabilizing p53. Here, we identify human HEATR1, as a nucleolar protein which positively regulates ribosomal RNA (rRNA) synthesis. Downregulation of HEATR1 resulted in cell cycle arrest in a manner dependent on p53. Moreover, depletion of HEATR1 also caused disruption of nucleolar structure and activated the ribosomal biogenesis stress pathway - RPL5 / RPL11 dependent stabilization and activation of p53. These findings reveal an important role for HEATR1 in ribosome biogenesis and further support the concept that perturbation of ribosome biosynthesis results in p53-dependent cell cycle checkpoint activation, with implications for human pathologies including cancer.

Keywords: HEATR1; cancer; p53; ribosome biogenesis; ribosome biogenesis stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Minor Histocompatibility Antigens / metabolism*
  • Nuclear Proteins / metabolism
  • Organelle Biogenesis*
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • RNA Polymerase I / genetics*
  • RNA, Ribosomal / biosynthesis
  • RNA-Binding Proteins / metabolism*
  • Ribosomal Proteins / metabolism*
  • Ribosomes / metabolism*
  • Signal Transduction
  • Stress, Physiological
  • Transcription, Genetic*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • HEATR1 protein, human
  • Minor Histocompatibility Antigens
  • Nuclear Proteins
  • RNA, Ribosomal
  • RNA-Binding Proteins
  • Ribosomal Proteins
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • RNA Polymerase I

Grants and funding

This work was supported by the Grant Agency of the Czech Republic under grants 17–14743S and 17–25976S, the MEYS CR (CZ.02.1.01/0.0/0.0/16_013/0001775 Czech-BioImaging), Czech National Program of Sustainability (LO1304), UP IGA_LF_2017_002, the Danish Cancer Society, the Danish Council for Independent Research, the Swedish Research Council, CancerFonden, the Lundbeck Foundation, and the Danish National Research Foundation (Center of Excellence, project CARD).Czech Science Foundation (GACR) [grant number 17-14743S]