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Science 5 November 1999:
Vol. 286. no. 5442, pp. 1162 - 1166
DOI: 10.1126/science.286.5442.1162
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Reports

Requirement of ATM-Dependent Phosphorylation of Brca1 in the DNA Damage Response to Double-Strand Breaks

David Cortez, 12 Yi Wang, 13 Jun Qin, 13 Stephen J. Elledge 124*

The Brca1 (breast cancer gene 1) tumor suppressor protein is phosphorylated in response to DNA damage. Results from this study indicate that the checkpoint protein kinase ATM (mutated in ataxia telangiectasia) was required for phosphorylation of Brca1 in response to ionizing radiation. ATM resides in a complex with Brca1 and phosphorylated Brca1 in vivo and in vitro in a region that contains clusters of serine-glutamine residues. Phosphorylation of this domain appears to be functionally important because a mutated Brca1 protein lacking two phosphorylation sites failed to rescue the radiation hypersensitivity of a Brca1-deficient cell line. Thus, phosphorylation of Brca1 by the checkpoint kinase ATM may be critical for proper responses to DNA double-strand breaks and may provide a molecular explanation for the role of ATM in breast cancer.

1 Verna and Mars McLean Department of Biochemistry and Molecular Biology,
2 Howard Hughes Medical Institute,
3 Department of Cell Biology,
4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
*   To whom correspondence should be addressed.

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J. Biol. Chem. 278, 9309-9317
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NFBD1/KIAA0170 Is a Chromatin-associated Protein Involved in DNA Damage Signaling Pathways.
X. Xu and D. F. Stern (2003)
J. Biol. Chem. 278, 8795-8803
   Abstract »    Full Text »    PDF »
Characterization of Arabidopsis thaliana ortholog of the human breast cancer susceptibility gene 1: AtBRCA1, strongly induced by gamma rays.
S. Lafarge and M.-H. Montane (2003)
Nucleic Acids Res. 31, 1148-1155
   Abstract »    Full Text »    PDF »
NFBD1, a Novel Nuclear Protein with Signature Motifs of FHA and BRCT, and an Internal 41-Amino Acid Repeat Sequence, Is an Early Participant in DNA Damage Response.
Y. L. Shang, A. J. Bodero, and P.-L. Chen (2003)
J. Biol. Chem. 278, 6323-6329
   Abstract »    Full Text »    PDF »
Cell Cycle Differences in DNA Damage-induced BRCA1 Phosphorylation Affect Its Subcellular Localization.
S. Okada and T. Ouchi (2003)
J. Biol. Chem. 278, 2015-2020
   Abstract »    Full Text »    PDF »
AtATM Is Essential for Meiosis and the Somatic Response to DNA Damage in Plants.
V. Garcia, H. Bruchet, D. Camescasse, F. Granier, D. Bouchez, and A. Tissier (2003)
PLANT CELL 15, 119-132
   Abstract »    Full Text »    PDF »
An ATR- and Chk1-Dependent S Checkpoint Inhibits Replicon Initiation following UVC-Induced DNA Damage.
T. P. Heffernan, D. A. Simpson, A. R. Frank, A. N. Heinloth, R. S. Paules, M. Cordeiro-Stone, and W. K. Kaufmann (2002)
Mol. Cell. Biol. 22, 8552-8561
   Abstract »    Full Text »    PDF »
hSnm1 Colocalizes and Physically Associates with 53BP1 before and after DNA Damage.
C. T. Richie, C. Peterson, T. Lu, W. N. Hittelman, P. B. Carpenter, and R. J. Legerski (2002)
Mol. Cell. Biol. 22, 8635-8647
   Abstract »    Full Text »    PDF »
Rare Variants of ATM and Risk for Hodgkin's Disease and Radiation-associated Breast Cancers.
K. Offit, S. Gilad, S. Paglin, P. Kolachana, L. C. Roisman, K. Nafa, V. Yeugelewitz, M. Gonzales, M. Robson, D. McDermott, et al. (2002)
Clin. Cancer Res. 8, 3813-3819
   Abstract »    Full Text »    PDF »
Regulation of BRCA1 Phosphorylation by Interaction with Protein Phosphatase 1{alpha}.
Y. Liu, D. M. Virshup, R. L. White, and L.-C. Hsu (2002)
Cancer Res. 62, 6357-6361
   Abstract »    Full Text »    PDF »
53BP1, a Mediator of the DNA Damage Checkpoint.
B. Wang, S. Matsuoka, P. B. Carpenter, and S. J. Elledge (2002)
Science 298, 1435-1438
   Abstract »    Full Text »    PDF »
S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51.
T. Taniguchi, I. Garcia-Higuera, P. R. Andreassen, R. C. Gregory, M. Grompe, and A. D. D'Andrea (2002)
Blood 100, 2414-2420
   Abstract »    Full Text »    PDF »
Chk2 Is a Tumor Suppressor That Regulates Apoptosis in both an Ataxia Telangiectasia Mutated (ATM)-Dependent and an ATM-Independent Manner.
A. Hirao, A. Cheung, G. Duncan, P.-M. Girard, A. J. Elia, A. Wakeham, H. Okada, T. Sarkissian, J. A. Wong, T. Sakai, et al. (2002)
Mol. Cell. Biol. 22, 6521-6532
   Abstract »    Full Text »    PDF »
Genetic and Environmental Determinants on Tissue Response to in Vitro Carcinogen Exposure and Risk of Breast Cancer.
D. Li, F. L. Walcott, P. Chang, W. Zhang, J. Zhu, E. Petrulis, S. E. Singletary, A. A. Sahin, and M. L. Bondy (2002)
Cancer Res. 62, 4566-4570
   Abstract »    Full Text »    PDF »
Phosphorylation of Serine 1387 in Brca1 Is Specifically Required for the Atm-mediated S-Phase Checkpoint after Ionizing Irradiation.
B. Xu, A. H. O'Donnell, S.-T. Kim, and M. B. Kastan (2002)
Cancer Res. 62, 4588-4591
   Abstract »    Full Text »    PDF »
BRCA1 Regulates the Interferon gamma -mediated Apoptotic Response.
H. N. Andrews, P. B. Mullan, S. McWilliams, S. Sebelova, J. E. Quinn, P. M. Gilmore, N. McCabe, A. Pace, B. Koller, P. G. Johnston, et al. (2002)
J. Biol. Chem. 277, 26225-26232
   Abstract »    Full Text »    PDF »
Constitutive Association of BRCA1 and c-Abl and Its ATM-Dependent Disruption after Irradiation.
N. Foray, D. Marot, V. Randrianarison, N. D. Venezia, D. Picard, M. Perricaudet, V. Favaudon, and P. Jeggo (2002)
Mol. Cell. Biol. 22, 4020-4032
   Abstract »    Full Text »    PDF »
Chk2 Activation and Phosphorylation-Dependent Oligomerization.
X. Xu, L. M. Tsvetkov, and D. F. Stern (2002)
Mol. Cell. Biol. 22, 4419-4432
   Abstract »    Full Text »    PDF »


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