DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway
DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway
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DOI：
10.1016/s1097-2765(00)80264-6
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发表时间：
2000-06-01
期刊：
影响因子：
16
通讯作者：
Alt, FW
中科院分区：
文献类型：
--
作者：
Frank, KM;Sharpless, NE;Alt, FW
DNA连接酶IV （LIG4）是一种非同源末端连接（NHEJ）蛋白，用于V(D)J重组和DNA修复。在小鼠中，Lig4缺乏导致胚胎死亡、大量神经元凋亡、淋巴细胞生成受阻和各种细胞缺陷。在此，我们评估了INK4a/ARF和p53这两种与细胞凋亡和衰老有关的蛋白在这种表型中的潜在作用。INK4a/ARF缺陷修复了lig4缺陷成纤维细胞的增殖/衰老缺陷，但没有修复其他表型方面的缺陷。相反，p53缺乏挽救了胚胎致死性、神经元凋亡和成纤维细胞增殖/衰老缺陷，但不能挽救淋巴细胞发育或放射敏感性。年轻的Lig4/p53双缺失小鼠通常死于前b型淋巴瘤。因此，在Lig4缺乏的情况下，胚胎致死和神经元凋亡可能是由于p53对未修复的DNA损伤的依赖反应，神经元凋亡和淋巴细胞发育缺陷可以在机制上分离。
DNA ligase IV (LIG4) is a nonhomologous end-joining (NHEJ) protein used for V(D)J recombination and DNA repair. In mice, Lig4 deficiency causes embryonic lethality, massive neuronal apoptosis, arrested lympho-genesis, and various cellular defects. Herein, we assess potential roles in this phenotype for INK4a/ARF and p53, two proteins implicated in apoptosis and senescence. INK4a/ARF deficiency rescued proliferation/senescence defects of Lig4-deficient fibroblasts but not other phenotypic aspects. In contrast, p53 deficiency rescued embryonic lethality, neuronal apoptosis, and fibroblast proliferation/senescence defects but not lymphocyte development or radiosensitivity. Young Lig4/p53 double null mice routinely died from pro-B lymphomas. Thus, in the context of Lig4 deficiency, embryonic lethality and neuronal apoptosis likely result from a p53-dependent response to unrepaired DNA damage, and neuronal apoptosis and lymphocyte developmental defects can be mechanistically dissociated.