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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway

Katherine M Hannan1, Priscilla Soo2, Mei S Wong3

  • 1ACRF Department of Cancer Biology and Therapeutics and Division of Genome Sciences and Cancer, John Curtin School of Medical Research, Australian National University, Acton, ACT 2601, Australia; Division of Research, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia.

Cell Reports
|November 2, 2022
PubMed

Insights

The nucleolar surveillance pathway integrates cellular stresses to control p53 levels. Ribosome biogenesis disruption strongly stabilizes p53, highlighting its role in stress response and proliferation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The nucleolar surveillance pathway regulates p53 levels in response to nucleolar stress.
  • Dysregulation of this pathway is linked to ribosomopathies and cancer.
  • The precise molecular mechanisms governing this pathway remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying the nucleolar surveillance pathway.
  • To identify key regulators of p53 accumulation in response to nucleolar stress.
  • To understand the connection between ribosome biogenesis and cellular stress responses.

Main Methods:

  • Genome-wide loss-of-function screens were employed to identify critical genes.
  • Functional assays were performed to assess pathway regulation.
  • Specific gene disruptions, including HEATR3, were analyzed.

Main Results:

  • Disruption of the ribosome biogenesis axis was identified as a potent stabilizer of p53.
  • HEATR3 was identified as a key regulator of the nucleolar surveillance pathway.
  • The nucleolar surveillance pathway is essential for p53 accumulation induced by various nuclear stresses, including DNA damage.

Conclusions:

  • The nucleolar surveillance pathway acts as a central integrator of cellular stresses affecting nuclear p53.
  • Ribosome biogenesis is intrinsically linked to cellular proliferative capacity through this pathway.
  • This pathway is a critical nexus connecting nucleolar integrity, stress sensing, and p53-mediated cell fate decisions.
Keywords:
CP: Molecular biologyhigh-content screeninghigh-throughput screeningnucleolar surveillance pathwaynucleolusp53ribosomal proteinsribosome biogenesisstress

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