Hypersensitivity to oxygen is a uniform and secondary defect in Fanconi anemia cells

Abstract

Cells from patients with Fanconi anemia (FA) frequently show an increased sensitivity to DNA crosslinking agents such as mitomycin C (MMC). FA cells also show abnormal sensitivity to oxygen tension. In order to examine the correlation between the two cellular defects in FA, several FA fibroblast lines were tested for their sensitivity to MMC and oxygen by colony-formation frequency. The sensitivity to MMC in different FA lines varied in a broad range from normal level to extreme hypersensitivity, whereas all of the FA lines showed similar hypersensitivity to oxygen. When FA fibroblasts were transformed by SV40 large T-antigen, the hypersensitivity to oxygen was normalized while the MMC sensitivity still remained. These results suggest that the cellular sensitivity to oxygen is a secondary defect rather than a primary effect of mutations in FA. However, it is a more uniform phenotype that the MMC sensitivity, and therefore, it may be closely related to the common clinical symptoms of FA. Since 1% oxygen showed the highest colony-formation frequency for FA cells, establishment of FA primary fibroblasts was attempted at the low oxygen condition. FA fibroblast cells showed greatly enhanced growth and migration at 1% oxygen resulting in fast establishment of FA primary fibroblasts.