BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage.
BRCA1 is a major player in the DNA damage response. This is evident from its loss, which causes cells to become sensitive to a wide variety of DNA damaging agents. The major BRCA1 binding partner, BARD1, is also implicated in the DNA damage response, and recent reports indicate that BRCA1 ... and BARD1 co-operate in this pathway. In this report, we utilized small interfering RNA to deplete BRCA1 and BARD1 to demonstrate that the BRCA1-BARD1 complex is required for ATM/ATR (ataxia-telangiectasia-mutated/ATM and Rad3-related)-mediated phosphorylation of p53(Ser-15) following IR- and UV radiation-induced DNA damage. In contrast, phosphorylation of a number of other ATM/ATR targets including H2AX, Chk2, Chk1, and c-jun does not depend on the presence of BRCA1-BARD1 complexes. Moreover, prior ATM/ATR-dependent phosphorylation of BRCA1 at Ser-1423 or Ser-1524 regulates the ability of ATM/ATR to phosphorylate p53(Ser-15) efficiently. Phosphorylation of p53(Ser-15) is necessary for an IR-induced G(1)/S arrest via transcriptional induction of the cyclin-dependent kinase inhibitor p21. Consistent with these data, repressing p53(Ser-15) phosphorylation by BRCA1-BARD1 depletion compromises p21 induction and the G(1)/S checkpoint arrest in response to IR but not UV radia-tion. These findings suggest that BRCA1-BARD1 complexes act as an adaptor to mediate ATM/ATR-directed phosphorylation of p53, influencing G(1)/S cell cycle progression after DNA damage.
Mesh Terms:
BRCA1 Protein, Base Sequence, Cell Cycle Proteins, Cell Line, DNA Damage, DNA Primers, DNA-Binding Proteins, Dimerization, G1 Phase, Hela Cells, Humans, Macromolecular Substances, Models, Biological, Phosphorylation, Protein-Serine-Threonine Kinases, RNA, Small Interfering, S Phase, Serine, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases
BRCA1 Protein, Base Sequence, Cell Cycle Proteins, Cell Line, DNA Damage, DNA Primers, DNA-Binding Proteins, Dimerization, G1 Phase, Hela Cells, Humans, Macromolecular Substances, Models, Biological, Phosphorylation, Protein-Serine-Threonine Kinases, RNA, Small Interfering, S Phase, Serine, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases
J. Biol. Chem.
Date: Jul. 23, 2004
PubMed ID: 15159397
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