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.

We are grateful to MH Sow, A Caillon and C Genet for technical help. We are specifically indebted to Dr A Major for supply and sharing of expertise in the NuTu-19 cell line. We are grateful

to G Del Sal for his generous gift of expression plasmids of the p53 mutants and T McDonnell for PC3 cell line. This work was supported by grant 3100-068222 from the Swiss National Science

Foundation to IIF and KHK.

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

Anis Feki, Charles Edward Jefford, Philip Berardi, Jian-Yu Wu, Laetitia Cartier, Karl-Heinz Krause & Irmgard Irminger-Finger

Department of Gynecology and Obstetrics, University Hospital of Geneva, Geneva, Switzerland

Biochemistry and Molecular Biology and Oncology, University of Calgary, Calgary, Canada

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