Title |
BRCA1-BARD1 Complexes Are Required for p53Ser-15 Phosphorylation and a G1/S Arrest following Ionizing Radiation-induced DNA Damage*
|
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Published in |
Journal of Biological Chemistry, May 2004
|
DOI | 10.1074/jbc.m405372200 |
Pubmed ID | |
Authors |
Megan Fabbro, Kienan Savage, Karen Hobson, Andrew J. Deans, Simon N. Powell, Grant A. McArthur, Kum Kum Khanna |
Abstract |
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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
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Russia | 1 | <1% |
Unknown | 107 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
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Researcher | 21 | 19% |
Student > Master | 14 | 13% |
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Student > Postgraduate | 6 | 5% |
Other | 13 | 12% |
Unknown | 22 | 20% |
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Immunology and Microbiology | 2 | 2% |
Other | 2 | 2% |
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