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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}mrc-lmb.cam.ac.uk


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