Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: The effects of ionizing radiation on growth, survival, and development
Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: The effects of ionizing radiation on growth, survival, and development
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DOI：
10.1073/pnas.94.25.13588
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发表时间：
1997-12-09
影响因子：
11.1
通讯作者：
Li, GC
中科院分区：
文献类型：
--
作者：
Nussenzweig, A;Sokol, K;Li, GC
我们最近发现，缺乏DNA依赖性蛋白激酶的86 kDa组分（Ku 80）的小鼠表现出生长迟缓和V（D）J（可变、多样性和连接）重组的严重缺陷。这些缺陷可能与DNA代谢异常有关，这些异常是由于Ku 80突变细胞无法处理DNA双链断裂而引起的。为了进一步表征Ku 80在DNA双链断裂修复中的腐烂，我们产生了胚胎干细胞和前B细胞，并检查了它们对电离辐射的反应。Ku 80（-/-）小鼠胚胎干细胞对γ射线的敏感性高于对照组，来源于Ku 80突变小鼠的前B细胞表现出更强的自发性和γ射线诱导的凋亡。我们随后测定了电离辐射对Ku 80缺陷小鼠存活、生长和淋巴细胞发育的影响，Ku 80（-/-）小鼠表现出对γ射线的超敏反应，其特征在于毛发色素沉着、胃肠道严重损伤和死亡率增加。新生Ku 80（-/-）小鼠暴露于亚致死剂量的电离辐射增强了其生长迟缓并导致T细胞特异性分化的诱导。然而，与严重联合免疫缺陷小鼠不同，Ku 80（-/-）小鼠辐射诱导的T细胞发育并不伴随广泛的胸腺细胞增殖。Ku 80缺陷细胞系和小鼠对DNA损伤剂的反应为Ku 80在生长调节、淋巴细胞发育、酸性DNA修复中的作用提供了重要的见解。
We recently have shown that mice deficient for the 86-kDa component (Ku80) of the DNA-dependent protein kinase exhibit growth retardation and a profound deficiency in V(D)J (variable, diversity, and joining) recombination. These defects may be related to abnormalities in DNA metabolism that arise from the inability of Ku80 mutant cells to process DNA double-strand breaks. To further characterize the rot of Ku80 in DNA double-strand break repair; we have generated embryonic stem cells and pre-B cells and examined their response to ionizing radiation. Ku80(-/-) embryonic stem cells are more sensitive than controls to gamma-irradiation, and pre-B cells derived from Ku80 mutant mice display enhanced spontaneous and gamma-ray-induced apoptosis, We then determined the effects of ionizing radiation on the survival, growth, and lymphocyte development in Ku80-deficient mice, Ku80(-/-) mice display a hypersensitivity to gamma-irradiation, characterized by toss of hair pigmentation, severe injury to the gastrointestinal tract, and enhanced mortality. Exposure of newborn Ku80(-/-) mice to sublethal doses of ionizing radiation enhances their growth retardation and results in the induction of T cell-specific differentiation, However, unlike severe combined immunodeficient mice, radiation-induced T cell development in Ku80(-/-) mice is not accompanied by extensive thymocyte proliferation. The response of Ku80-deficient: cell lines and mice to DNA-damaging agents provides important insights into the role of Ku80 in growth regulation, lymphocyte development, acid DNA repair.