Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence

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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

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

Published on: August 4, 2019

Emma Langley1, Mark Pearson, Mario Faretta

  • 1Wellcome Institute/Cancer Research UK and Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QR, UK.

The EMBO Journal
|May 15, 2002
PubMed

Insights

The human Sir2 homolog, SIRT1, deacetylates and represses p53, a key protein in cellular senescence. SIRT1 antagonizes PML-induced p53 acetylation, rescuing premature cellular senescence.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Epigenetics

Background:

  • The yeast Sir2 protein is a conserved NAD-dependent histone deacetylase regulating lifespan.
  • SIRT1 is the human homolog of yeast Sir2.
  • p53 is a crucial tumor suppressor protein involved in cellular senescence.

Purpose of the Study:

  • To investigate the role of human SIRT1 in mammalian cells.
  • To determine if SIRT1 interacts with p53 and modulates its function.
  • To explore SIRT1's role in cellular senescence.

Main Methods:

  • Overexpression of PML or oncogenic Ras (Ha-rasV12) in mammalian cells.
  • Co-immunoprecipitation to assess protein interactions.
  • Western blotting to detect protein acetylation.
  • Cellular senescence assays.

Main Results:

  • SIRT1 is recruited to PML nuclear bodies upon PML or Ha-rasV12 overexpression.
  • SIRT1 binds to and deacetylates p53.
  • SIRT1 represses p53-mediated transactivation.
  • SIRT1 antagonizes PML-induced p53 acetylation and rescues PML-mediated premature cellular senescence.

Conclusions:

  • SIRT1 is a novel negative regulator of p53 function.
  • SIRT1 deacetylase activity modulates cellular senescence.
  • SIRT1 plays a critical role in the regulation of p53 and cellular senescence pathways.

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