BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase.
The BRCA1-associated RING domain protein BARD1 acts with BRCA1 in double-strand break repair and ubiquitination. BARD1 plays a role as mediator of apoptosis by binding to and stabilizing p53, and BARD1-repressed cells are resistant to apoptosis. We therefore investigated the mechanism by which BARD1 induces p53 stability and apoptosis. The apoptotic activity of p53 is regulated by phosphorylation. We demonstrate that BARD1 binds to unphosphorylated and serine-15 phosphorylated forms of p53 in several cell types and that the region required for binding comprises the region sufficient for apoptosis induction. In addition, BARD1 binds to Ku-70, the regulatory subunit of DNA-PK, suggesting that the mechanism of p53-induced apoptosis requires BARD1 for the phosphorylation of p53. Upregulation of BARD1 alone is sufficient for stabilization of p53 and phosphorylation on serine-15, as shown in nonmalignant epithelial cells and ovarian cancer cells, NuTu-19, which are defective in apoptosis induction and express aberrant splice variants of BARD1. Stabilization and phosphorylation of p53 in NuTu-19 cells, as well as apoptosis, can be induced by the exogenous expression of wild-type BARD1, suggesting that BARD1, by binding to the kinase and its substrate, catalyses p53 phosphorylation.
Feki
Anis
A
Biology of Aging Laboratory, Department of Geriatrics, University of Geneva, Chemin de Petit Bel Air 2, CH-1225 Geneva/Chêne-Bourg, Switzerland.
Jefford
Charles Edward
CE
Berardi
Philip
P
Wu
Jian-Yu
JY
Cartier
Laetitia
L
Krause
Karl-Heinz
KH
Irminger-Finger
Irmgard
I
D000595:Amino Acid Sequence; D017209:Apoptosis; D002384:Catalysis; D002460:Cell Line; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases