SCID MUTATION IN MICE CONFERS HYPERSENSITIVITY TO IONIZING-RADIATION AND A DEFICIENCY IN DNA DOUBLE-STRAND BREAK REPAIR
SCID MUTATION IN MICE CONFERS HYPERSENSITIVITY TO IONIZING-RADIATION AND A DEFICIENCY IN DNA DOUBLE-STRAND BREAK REPAIR
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DOI：
10.1073/pnas.88.4.1394
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发表时间：
1991-02-01
影响因子：
11.1
通讯作者：
BROWN, JM
中科院分区：
文献类型：
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作者：
BIEDERMANN, KA;SUN, JR;BROWN, JM
C.B-17严重联合免疫缺陷（scid）小鼠携带scid突变，并且在T细胞和B细胞介导的免疫中严重缺陷，这显然是由于免疫球蛋白和T细胞受体基因元件的V（D）J连接缺陷。在目前的研究中，我们已经确定了这些小鼠的另一个特征的组织，细胞和分子基础：它们对电离辐射的超敏反应。scid小鼠的骨髓干细胞、肠隐窝细胞和上皮皮肤细胞在原位照射时比同类BALB/c或C.B-17对照敏感2- 3倍。两个独立分离的胚胎成纤维细胞scid小鼠细胞系对γ射线表现出相似的超敏反应。此外，这些细胞系对博来霉素的细胞杀伤敏感，博来霉素也产生DNA链断裂，但对DNA交联剂丝裂霉素C或UV照射不敏感。脉冲场凝胶电泳测量γ射线诱导的DNA双链断裂的重新连接表明，这些动物在这个修复系统中有缺陷。这表明scid小鼠成纤维细胞的γ射线敏感性可能是DNA双链断裂修复减少的结果。因此，一个共同因子可能参与淋巴细胞发育过程中DNA双链断裂的修复以及V（D）J重新连接。这种小鼠常染色体隐性突变应被证明是非常有用的辐射诱导的DNA损伤和修复的基础研究。
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.