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PMID:15782130

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Citation

Feki, A, Jefford, CE, Berardi, P, Wu, JY, Cartier, L, Krause, KH and Irminger-Finger, I (2005) BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase. Oncogene 24:3726-36

Abstract

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.

Links

PubMed Online version:10.1038/sj.onc.1208491

Keywords

Amino Acid Sequence; Apoptosis; Catalysis; Cell Line; DNA Damage; DNA-Activated Protein Kinase; DNA-Binding Proteins/physiology; Green Fluorescent Proteins/metabolism; Humans; Molecular Sequence Data; Nuclear Proteins; Phosphorylation; Protein-Serine-Threonine Kinases/physiology; Tumor Suppressor Protein p53/metabolism; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/physiology; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:P53

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12956

F

Seeded From UniProt

complete

HUMAN:XRCC6

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P04637

F

Seeded From UniProt

complete

HUMAN:Q761V2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99728

F

Seeded From UniProt

complete

HUMAN:BARD1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q761V2

F

Seeded From UniProt

complete

HUMAN:BARD1

involved_in

GO:0001894: tissue homeostasis

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BARD1

enables

GO:0019900: kinase binding

ECO:0000303: author statement without traceable support used in manual assertion

F

Seeded From UniProt

complete

HUMAN:BARD1

involved_in

GO:0043065: positive regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BARD1

involved_in

GO:0042325: regulation of phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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