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BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase

Anis Feki1, Charles Edward Jefford, Philip Berardi

  • 1Biology of Aging Laboratory, Department of Geriatrics, University of Geneva, Chemin de Petit Bel Air 2, CH-1225 Geneva/Chêne-Bourg, Switzerland.

Oncogene
|March 23, 2005
PubMed

Insights

BRCA1-associated RING domain protein BARD1 stabilizes p53, inducing apoptosis. BARD1 facilitates p53 phosphorylation by binding to the kinase and substrate, crucial for cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • BRCA1-associated RING domain protein BARD1 (BARD1) is crucial for DNA repair and ubiquitination.
  • BARD1 mediates apoptosis by stabilizing p53, a key tumor suppressor.
  • Dysfunctional BARD1 leads to apoptosis resistance.

Purpose of the Study:

  • To elucidate the mechanism by which BARD1 induces p53 stability and apoptosis.
  • To investigate the role of BARD1 in p53 phosphorylation and subsequent apoptosis induction.

Main Methods:

  • Co-immunoprecipitation assays to detect protein-protein interactions.
  • Analysis of p53 phosphorylation at serine-15.
  • Exogenous expression of wild-type BARD1 in cancer cells with BARD1 defects.

Main Results:

  • BARD1 binds to both unphosphorylated and serine-15 phosphorylated p53.
  • BARD1 interacts with Ku-70, suggesting a role in DNA-PK mediated p53 phosphorylation.
  • Upregulation of BARD1 alone stabilizes p53 and induces serine-15 phosphorylation.
  • Restoration of wild-type BARD1 in defective cells re-establishes p53 stabilization, phosphorylation, and apoptosis.

Conclusions:

  • BARD1 acts as a catalyst for p53 phosphorylation, essential for apoptosis induction.
  • BARD1's interaction with both p53 and DNA-PK components facilitates this process.
  • Defects in BARD1 can impair apoptosis, highlighting its therapeutic potential in cancer.

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