PURPOSE: Individuals suffering from Fanconi Anemia (FA) exhibit a pronounced hypersensitivity to agents that cause DNA inter-strand crosslinks and frequently also to ionising radiation. However, fibroblast lines derived from FA patients generally show little or no radiosensitivity in vitro. Here, we sought to elucidate the role of the central FA protein D2 (FANCD2) in determining cellular radioresistance. MATERIAL AND METHODS: Clonogenic radiation survival was assessed in an isogenic pair of human fibroblasts with or without wild-type FANCD2 under varying oxygen concentrations. Additional endpoints included single-cell gel electrophoresis, RAD51 foci formation, and apoptosis. RESULTS: At 20% oxygen, there was no reduction in the survival of FANCD2-deficient fibroblasts compared to wild-type complemented cells. However, at 0% oxygen FANCD2-deficient cells were more radiosensitive than wild-type cells. Interestingly, at 3% oxygen, which more closely resembles the physiological environment in human tissues, the difference in radiosensitivity was maintained. Our data also suggest that the increased radiosensitivity of FANCD2-deficient cells seen under conditions of reduced oxygen is associated with apoptotic cell death, but not secondary to a defect in the homologous recombination repair pathway that is required for crosslink repair. CONCLUSIONS: Our data may help explain the previously described discrepancy between the clinical and cellular radiosensitivity of FA patients.
PURPOSE: Individuals suffering from Fanconi Anemia (FA) exhibit a pronounced hypersensitivity to agents that cause DNA inter-strand crosslinks and frequently also to ionising radiation. However, fibroblast lines derived from FA patients generally show little or no radiosensitivity in vitro. Here, we sought to elucidate the role of the central FA protein D2 (FANCD2) in determining cellular radioresistance. MATERIAL AND METHODS: Clonogenic radiation survival was assessed in an isogenic pair of human fibroblasts with or without wild-type FANCD2 under varying oxygen concentrations. Additional endpoints included single-cell gel electrophoresis, RAD51 foci formation, and apoptosis. RESULTS: At 20% oxygen, there was no reduction in the survival of FANCD2-deficient fibroblasts compared to wild-type complemented cells. However, at 0% oxygenFANCD2-deficient cells were more radiosensitive than wild-type cells. Interestingly, at 3% oxygen, which more closely resembles the physiological environment in human tissues, the difference in radiosensitivity was maintained. Our data also suggest that the increased radiosensitivity of FANCD2-deficient cells seen under conditions of reduced oxygen is associated with apoptotic cell death, but not secondary to a defect in the homologous recombination repair pathway that is required for crosslink repair. CONCLUSIONS: Our data may help explain the previously described discrepancy between the clinical and cellular radiosensitivity of FA patients.
Authors: Hebist Berhane; Michael W Epperly; Julie Goff; Ronny Kalash; Shaonan Cao; Darcy Franicola; Xichen Zhang; Donna Shields; Frank Houghton; Hong Wang; Peter Wipf; Kalindi Parmar; Joel S Greenberger Journal: Radiat Res Date: 2014-01-07 Impact factor: 2.841
Authors: Moritz Birkelbach; Natalie Ferraiolo; Liliana Gheorghiu; Heike N Pfäffle; Benedict Daly; Michael I Ebright; Cheryl Spencer; Carl O'Hara; Johnathan R Whetstine; Cyril H Benes; Lecia V Sequist; Lee Zou; Jochen Dahm-Daphi; Lisa A Kachnic; Henning Willers Journal: J Thorac Oncol Date: 2013-03 Impact factor: 15.609
Authors: Xinzhu Deng; Jason Tchieu; Daniel S Higginson; Kuo-Shun Hsu; Regina Feldman; Lorenz Studer; Shai Shaham; Simon N Powell; Zvi Fuks; Richard Kolesnick Journal: Cancer Res Date: 2021-05-03 Impact factor: 12.701