scid Mutation in Mice Confers Hypersensitivity to Ionizing Radiation and a Deficiency in DNA Double-Strand Break Repair

• Published in: Proceedings of the National Academy of Sciences - PNAS 1991-02, Vol.88 (4), p.1394-1397
• Main Authors: Biedermann, Kim A., Sun, Jirong, Giaccia, Amato J., Tosto, Liana M., Brown, J. Martin
• Format: Article
• Language: English
• Subjects: 560120 - Radiation Effects on Biochemicals, Cells, & Tissue Culture; ANIMAL CELLS; ANIMALS; ANTI-INFECTIVE AGENTS; ANTIBIOTICS; ANTIMITOTIC DRUGS; ANTINEOPLASTIC DRUGS; B lymphocytes; Biological and medical sciences; BIOLOGICAL RECOVERY; BIOLOGICAL REPAIR; BLEOMYCIN; Bone marrow cells; CELL KILLING; Cell lines; Cell Survival - radiation effects; Cells; Cells, Cultured; Classical genetics, quantitative genetics, hybrids; CONNECTIVE TISSUE CELLS; DNA - radiation effects; DNA Damage; DNA REPAIR; Dose-Response Relationship, Radiation; DOSE-RESPONSE RELATIONSHIPS; DRUGS; ELECTROMAGNETIC RADIATION; ELECTROPHORESIS; Epithelial cells; FIBROBLASTS; Fibroblasts - radiation effects; Fundamental and applied biological sciences. Psychology; GAMMA RADIATION; Gamma Rays; GENE MUTATIONS; Genetics of eukaryotes. Biological and molecular evolution; IMMUNITY; Immunologic Deficiency Syndromes - genetics; IONIZING RADIATIONS; Lymphocytes; MAMMALS; MICE; Mice, Inbred BALB C; Mice, Inbred Strains; Mice, Mutant Strains; Mutation; MUTATIONS; Myeloid cells; Organ Specificity; Radiation tolerance; RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT; RADIATIONS; RADIOSENSITIVITY; RECESSIVE MUTATIONS; RECOVERY; REPAIR; RODENTS; SOMATIC CELLS; Species Specificity; STEM CELLS; STRAND BREAKS; Vertebrata; VERTEBRATES
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.88.4.1394

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 γ-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 γ-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 γ-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.