scid mutation in mice confers hypersensitivity to ionizing radiation and a deficiency in DNA double-strand break repair.
C.B-17 severe combined immunodeficient (scid) mice carry the scid mutation and are severely deficient in both T cell- and B cell-mediated immunity, apparently as a result of defective V(D)J joining of the immunoglobulin and T-cell receptor gene elements. In the present studies, we have defined the tissue, cellular, and molecular basis of another characteristic of these mice: their hypersensitivity to ionizing radiation. Bone marrow stem cells, intestinal crypt cells, and epithelial skin cells from scid mice are 2- to 3-fold more sensitive when irradiated in situ than are congenic BALB/c or C.B-17 controls. Two independently isolated embryo fibroblastic scid mouse cell lines display similar hypersensitivities to gamma-rays. In addition, these cell lines are sensitive to cell killing by bleomycin, which also produces DNA strand breaks, but not by the DNA crosslinking agent mitomycin C or UV irradiation. Measurement of the rejoining of gamma-ray-induced DNA double-strand breaks by pulsed-field gel electrophoresis indicates that these animals are defective in this repair system. This suggests that the gamma-ray sensitivity of the scid mouse fibroblasts could be the result of reduced repair of DNA double-strand breaks. Therefore, a common factor may participate in both the repair of DNA double-strand breaks as well as V(D)J rejoining during lymphocyte development. This murine autosomal recessive mutation should prove extremely useful in fundamental studies of radiation-induced DNA damage and repair.
Biedermann
K A
KA
Department of Radiation Oncology, Stanford University Medical Center, CA 94305.
Sun
J R
JR
Giaccia
A J
AJ
Tosto
L M
LM
Brown
J M
JM
D000818:Animals; D002470:Cell Survival / Q000528:radiation effects; D002478:Cells, Cultured; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000528:radiation effects; D005720:Gamma Rays; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009154:Mutation; D009928:Organ Specificity; D013045:Species Specificity
D004247:DNA