Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway.
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.
Pace
Paul
P
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
Mosedale
Georgina
G
Hodskinson
Michael R
MR
Rosado
Ivan V
IV
Sivasubramaniam
Meera
M
Patel
Ketan J
KJ
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002645:Chickens; D019457:Chromosome Breakage; D003432:Cross-Linking Reagents / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics* / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005785:Gene Conversion; D005803:Genes, Immunoglobulin; D006801:Humans; D007075:Immunoglobulin M / Q000235:genetics; D000072200:Ku Autoantigen; D017354:Point Mutation; D011994:Recombinant Proteins / Q000378:metabolism; D011995:Recombination, Genetic
D034961:Antigens, Nuclear; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; C499905:FANCD2 protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D007075:Immunoglobulin M; D011994:Recombinant Proteins; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen