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Published online 15 June 2004

Nucleic Acids Research, 2004, Vol. 32, No. 10 3248-3257
© 2004 Nucleic Acids Research, Vol. 32 No. 10 © Oxford University Press 2004; all rights reserved

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

Sarah L. Donahue and Colin Campbell*

Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455, USA

* To whom correspondence should be addressed. Tel: +1 612 625 8986; Fax: +1 612 625 8408; Email: campb034{at}umn.edu
Present address: Sarah L. Donahue, Department of Microbiology and Immunology, Vanderbilt University Medical Center, AA-4210 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232, USA

Received March 15, 2004; Accepted May 20, 2004

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.


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