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Science 329 (5988): 219-223

Copyright © 2010 by the American Association for the Advancement of Science

Ku70 Corrupts DNA Repair in the Absence of the Fanconi Anemia Pathway

Paul Pace,1,* Georgina Mosedale,2,* Michael R. Hodskinson,1,* Ivan V. Rosado,1 Meera Sivasubramaniam,1 Ketan J. Patel1,{dagger}

Abstract: A conserved DNA repair response is defective in the human genetic illness Fanconi anemia (FA). Mutation of some FA genes impairs homologous recombination and error-prone DNA repair, rendering FA cells sensitive to DNA cross-linking agents. We found a genetic interaction between the FA gene FANCC and the nonhomologous end joining (NHEJ) factor Ku70. Disruption of both FANCC and Ku70 suppresses sensitivity to cross-linking agents, diminishes chromosome breaks, and reverses defective homologous recombination. Ku70 binds directly to free DNA ends, committing them to NHEJ repair. We show that purified FANCD2, a downstream effector of the FA pathway, might antagonize Ku70 activity by modifying such DNA substrates. These results reveal a function for the FA pathway in processing DNA ends, thereby diverting double-strand break repair away from abortive NHEJ and toward homologous recombination.

1 MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
2 Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: kjp{at}

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K. Sato, M. Ishiai, K. Toda, S. Furukoshi, A. Osakabe, H. Tachiwana, Y. Takizawa, W. Kagawa, H. Kitao, N. Dohmae, et al. (2012)
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   Abstract »    Full Text »    PDF »
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A. Rodriguez, D. Sosa, L. Torres, B. Molina, S. Frias, and L. Mendoza (2012)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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C. Hodson, A. R. Cole, L. P. C. Lewis, J. A. Miles, A. Purkiss, and H. Walden (2011)
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   Abstract »    Full Text »    PDF »
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J. Murai, K. Yang, D. Dejsuphong, K. Hirota, S. Takeda, and A. D. D'Andrea (2011)
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   Abstract »    Full Text »    PDF »
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C. Cotta-Ramusino, E. R. McDonald III, K. Hurov, M. E. Sowa, J. W. Harper, and S. J. Elledge (2011)
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   Abstract »    Full Text »    PDF »
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J.-H. Guervilly, E. Renaud, M. Takata, and F. Rosselli (2011)
Hum. Mol. Genet. 20, 2171-2181
   Abstract »    Full Text »    PDF »
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S. Zhang, H. Yajima, H. Huynh, J. Zheng, E. Callen, H.-T. Chen, N. Wong, S. Bunting, Y.-F. Lin, M. Li, et al. (2011)
J. Cell Biol. 193, 295-305
   Abstract »    Full Text »    PDF »
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K. A. Coleman and R. A. Greenberg (2011)
J. Biol. Chem. 286, 13669-13680
   Abstract »    Full Text »    PDF »
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A. G. Patel, J. N. Sarkaria, and S. H. Kaufmann (2011)
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Ku prevents Exo1 and Sgs1-dependent resection of DNA ends in the absence of a functional MRX complex or Sae2.
E. P. Mimitou and L. S. Symington (2010)
EMBO J. 29, 3358-3369
   Abstract »    Full Text »    PDF »
Expanded roles of the Fanconi anemia pathway in preserving genomic stability.
Y. Kee and A. D. D'Andrea (2010)
Genes & Dev. 24, 1680-1694
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