ATM与非同源末端连接因子在基因组稳定性和发育过程中的遗传相互作用。
Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development.
作者信息
Sekiguchi J, Ferguson D O, Chen H T, Yang E M, Earle J, Frank K, Whitlow S, Gu Y, Xu Y, Nussenzweig A, Alt F W
机构信息
The Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3243-8. doi: 10.1073/pnas.051632098. Epub 2001 Mar 6.
DNA ligase IV (Lig4) and the DNA-dependent protein kinase (DNA-PK) function in nonhomologous end joining (NHEJ). However, although Lig4 deficiency causes late embryonic lethality, deficiency in DNA-PK subunits (Ku70, Ku80, and DNA-PKcs) does not. Here we demonstrate that, similar to p53 deficiency, ataxia-telangiectasia-mutated (ATM) gene deficiency rescues the embryonic lethality and neuronal apoptosis, but not impaired lymphocyte development, associated with Lig4 deficiency. However, in contrast to p53 deficiency, ATM deficiency enhances deleterious effects of Lig4 deficiency on growth potential of embryonic fibroblasts (MEFs) and genomic instability in both MEFs and cultured progenitor lymphocytes, demonstrating significant differences in the interplay of p53 vs. ATM with respect to NHEJ. Finally, in dramatic contrast to effects on Lig4 deficiency, ATM deficiency causes early embryonic lethality in Ku- or DNA-PKcs-deficient mice, providing evidence for an NHEJ-independent role for the DNA-PK holoenzyme.
DNA连接酶IV（Lig4）和DNA依赖性蛋白激酶（DNA-PK）在非同源末端连接（NHEJ）过程中发挥作用。然而，尽管Lig4缺陷会导致胚胎后期致死，但DNA-PK亚基（Ku70、Ku80和DNA-PKcs）缺陷却不会。在此我们证明，与p53缺陷类似，共济失调毛细血管扩张症突变（ATM）基因缺陷可挽救与Lig4缺陷相关的胚胎致死和神经元凋亡，但不能挽救受损的淋巴细胞发育。然而，与p53缺陷不同的是，ATM缺陷增强了Lig4缺陷对胚胎成纤维细胞（MEF）生长潜能以及MEF和培养的祖代淋巴细胞基因组不稳定性的有害影响，这表明在NHEJ方面p53与ATM的相互作用存在显著差异。最后，与对Lig4缺陷的影响形成鲜明对比的是，ATM缺陷在Ku或DNA-PKcs缺陷小鼠中导致早期胚胎致死，这为DNA-PK全酶的非NHEJ依赖性作用提供了证据。
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