A Rad50-dependent pathway of DNA repair is deficient in Fanconi anemia fibroblasts.
Fanconi anemia (FA) is a fatal genetic disorder associated with pancytopenia and cancer. Cells lacking functional FA genes are hypersensitive to bifunctional alkylating agents, and are deficient in DNA double-strand break repair. Multiple genes with FA-causing mutations have been cloned, however, the molecular basis for FA remains obscure. The results presented herein indicate that a Rad50-dependent end-joining process is non-functional in diploid fibroblasts from FA patients. Introduction of anti-Rad50 antibody into normal fibroblasts sensitized them to DNA damaging agents, whereas this treatment had no effect on fibroblasts from FA patients. The DNA end-joining process deficient in FA cells also requires the Mre11, Nbs1 and DNA ligase IV proteins. These data reveal the existence of a previously uncharacterized Rad50-dependent DNA double-strand break repair pathway in mammalian somatic cells, and suggest that failure to activate this pathway is responsible, at least in part, for the defective DNA end-joining observed in FA cells.
Donahue
Sarah L
SL
Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455, USA.
Campbell
Colin
C
D017766:Acid Anhydride Hydrolases; D018797:Cell Cycle Proteins / Q000502:physiology; D002460:Cell Line; D004249:DNA Damage; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D005199:Fanconi Anemia / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins / Q000502:physiology; D015398:Signal Transduction
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C000607893:LIG4 protein, human; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D011088:DNA Ligases; D045643:DNA Repair Enzymes; D000072481:DNA Ligase ATP