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Science 6 June 2003:
Vol. 300. no. 5625, pp. 1542 - 1548
DOI: 10.1126/science.1083430
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Research Articles

Sensing DNA Damage Through ATRIP Recognition of RPA-ssDNA Complexes

Lee Zou1,2 and Stephen J. Elledge1,2,3*

The function of the ATR (ataxia-telangiectasia mutated– and Rad3-related)–ATRIP (ATR-interacting protein) protein kinase complex is crucial for the cellular response to replication stress and DNA damage. Here, we show that replication protein A (RPA), a protein complex that associates with single-stranded DNA (ssDNA), is required for the recruitment of ATR to sites of DNA damage and for ATR-mediated Chk1 activation in human cells. In vitro, RPA stimulates the binding of ATRIP to ssDNA. The binding of ATRIP to RPA-coated ssDNA enables the ATR-ATRIP complex to associate with DNA and stimulates phosphorylation of the Rad17 protein that is bound to DNA. Furthermore, Ddc2, the budding yeast homolog of ATRIP, is specifically recruited to double-strand DNA breaks in an RPA-dependent manner. A checkpoint-deficient mutant of RPA, rfa1-t11, is defective for recruiting Ddc2 to ssDNA both in vivo and in vitro. Our data suggest that RPA-coated ssDNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling.

1 Verna & Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
2 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

* To whom correspondence should be addressed. E-mail: selledge{at}bcm.tmc.edu

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Heterochromatin is refractory to {gamma}-H2AX modification in yeast and mammals.
J.-A. Kim, M. Kruhlak, F. Dotiwala, A. Nussenzweig, and J. E. Haber (2007)
J. Cell Biol. 178, 209-218
   Abstract »    Full Text »    PDF »
The yeast DNA damage checkpoint proteins control a cytoplasmic response to DNA damage.
F. Dotiwala, J. Haase, A. Arbel-Eden, K. Bloom, and J. E. Haber (2007)
PNAS 104, 11358-11363
   Abstract »    Full Text »    PDF »
Phosphorylation of ATR-Interacting Protein on Ser239 Mediates an Interaction with Breast-Ovarian Cancer Susceptibility 1 and Checkpoint Function.
M. Venere, A. Snyder, O. Zgheib, and T. D. Halazonetis (2007)
Cancer Res. 67, 6100-6105
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The Rad9-Hus1-Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1.
S. Delacroix, J. M. Wagner, M. Kobayashi, K.-i. Yamamoto, and L. M. Karnitz (2007)
Genes & Dev. 21, 1472-1477
   Abstract »    Full Text »    PDF »
Ataxia-telangiectasia Mutated (ATM)-dependent Activation of ATR Occurs through Phosphorylation of TopBP1 by ATM.
H. Y. Yoo, A. Kumagai, A. Shevchenko, A. Shevchenko, and W. G. Dunphy (2007)
J. Biol. Chem. 282, 17501-17506
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