Document Detail


FANCD2-deficient human fibroblasts are hypersensitive to ionising radiation at oxygen concentrations of 0% and 3% but not under normoxic conditions.
MedLine Citation:
PMID:  19466639     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Verena M Kuhnert; Lisa A Kachnic; Li Li; Martin Purschke; Liliana Gheorghiu; Richard Lee; Kathryn D Held; Henning Willers
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of radiation biology     Volume:  85     ISSN:  0955-3002     ISO Abbreviation:  Int. J. Radiat. Biol.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-05-25     Completed Date:  2009-08-12     Revised Date:  2013-09-04    
Medline Journal Info:
Nlm Unique ID:  8809243     Medline TA:  Int J Radiat Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  523-31     Citation Subset:  IM; S    
Affiliation:
Department of Radiation Oncology, University of Lübeck, Lübeck, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anoxia / metabolism
Apoptosis / radiation effects
Cell Line
Fanconi Anemia Complementation Group D2 Protein / deficiency*,  metabolism
Fibroblasts / drug effects,  enzymology*,  metabolism,  radiation effects*
Humans
Oxygen / pharmacology*
Rad51 Recombinase / genetics
Radiation Tolerance* / genetics
Radiation, Ionizing
Recombination, Genetic / radiation effects
Reproducibility of Results
Grant Support
ID/Acronym/Agency:
P01 CA095227/CA/NCI NIH HHS; P01 CA095227/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Fanconi Anemia Complementation Group D2 Protein; 7782-44-7/Oxygen; EC 2.7.7.-/Rad51 Recombinase
Comments/Corrections

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