A Rad50-dependent pathway of DNA repair is deficient in Fanconi anemia fibroblasts

• Published in: Nucleic acids research Vol. 32; no. 10; pp. 3248 - 3257
• Main Authors: Donahue, Sarah L., Campbell, Colin
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 2004; Oxford Publishing Limited (England)
• Subjects: Acid Anhydride Hydrolases; Cell Cycle Proteins - physiology; Cell Line; DNA Damage; DNA Ligase ATP; DNA Ligases - metabolism; DNA Repair; DNA Repair Enzymes - physiology; DNA-Binding Proteins - physiology; Fanconi Anemia - enzymology; Fanconi Anemia - genetics; Fanconi Anemia - metabolism; Fibroblasts - drug effects; Fibroblasts - enzymology; Humans; MRE11 Homologue Protein; Nuclear Proteins - physiology; Signal Transduction
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gkh649

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.