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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Nuclear / genetics*
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Antigens, Nuclear / metabolism
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Cell Line
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Chickens
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Chromosome Breakage
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Cross-Linking Reagents / pharmacology
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DNA Breaks, Double-Stranded*
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DNA Repair*
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Fanconi Anemia Complementation Group C Protein / genetics*
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Fanconi Anemia Complementation Group C Protein / metabolism
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Fanconi Anemia Complementation Group D2 Protein / chemistry
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Fanconi Anemia Complementation Group D2 Protein / genetics
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Fanconi Anemia Complementation Group D2 Protein / metabolism*
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Gene Conversion
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Genes, Immunoglobulin
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Humans
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Immunoglobulin M / genetics
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Ku Autoantigen
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Point Mutation
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Recombinant Proteins / metabolism
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Recombination, Genetic*
Substances
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Antigens, Nuclear
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Cross-Linking Reagents
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DNA-Binding Proteins
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FANCC protein, human
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FANCD2 protein, human
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Fanconi Anemia Complementation Group C Protein
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Fanconi Anemia Complementation Group D2 Protein
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Immunoglobulin M
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Recombinant Proteins
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Xrcc6 protein, human
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Ku Autoantigen