Loss of ATM kinase activity leads to embryonic lethality in mice.
Loss of ATM kinase activity leads to embryonic lethality in mice.
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DOI：
10.1083/jcb.201204035
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发表时间：
2012-08-06
期刊：
影响因子：
--
通讯作者：
Nussenzweig A
中科院分区：
文献类型：
--
作者：
Daniel JA;Pellegrini M;Lee BS;Guo Z;Filsuf D;Belkina NV;You Z;Paull TT;Sleckman BP;Feigenbaum L;Nussenzweig A
与ATM缺失小鼠相反，表达激酶死亡ATM变体的小鼠表现出胚胎致死性，与同源重组的更大缺陷相关。共济失调毛细血管扩张症（ATM）是一种重要的脱氧核糖核酸（DNA）损伤信号激酶，调节DNA修复、细胞周期检查点和细胞凋亡。大多数患有A-T（一种易患癌症的神经退行性疾病）的患者存在Atm的无效突变。为了确定ATM的功能是否仅由其激酶活性介导，我们产生了两个小鼠模型，其中包含单个的、催化失活的ATM点突变。在本文中，我们表明，在相反的Atm-null小鼠，D2899 A和Q2740 P突变导致小鼠早期胚胎致死，而不显示显性负干扰活性。使用条件性缺失，我们发现，D2899 A突变在成年小鼠的行为很大程度上类似于ATM-空细胞，但显示更大的缺陷，在同源重组（HR）的测量超敏反应聚（腺苷二磷酸-核糖）聚合酶抑制和增加基因组的不稳定性。这些结果可以解释为什么在经典A-T患者中很少发现没有可检测到的激酶活性的错义突变。我们认为，ATM激酶失活的错义突变，除非另行补偿，否则会干扰胚胎发生期间的HR。
In contrast to ATM-null mice, mice expressing a kinase-dead ATM variant exhibit embryonic lethality, associated with greater deficiency in homologous recombination. Ataxia telangiectasia (A-T) mutated (ATM) is a key deoxyribonucleic acid (DNA) damage signaling kinase that regulates DNA repair, cell cycle checkpoints, and apoptosis. The majority of patients with A-T, a cancer-prone neurodegenerative disease, present with null mutations in Atm. To determine whether the functions of ATM are mediated solely by its kinase activity, we generated two mouse models containing single, catalytically inactivating point mutations in Atm. In this paper, we show that, in contrast to Atm-null mice, both D2899A and Q2740P mutations cause early embryonic lethality in mice, without displaying dominant-negative interfering activity. Using conditional deletion, we find that the D2899A mutation in adult mice behaves largely similar to Atm-null cells but shows greater deficiency in homologous recombination (HR) as measured by hypersensitivity to poly (adenosine diphosphate-ribose) polymerase inhibition and increased genomic instability. These results may explain why missense mutations with no detectable kinase activity are rarely found in patients with classical A-T. We propose that ATM kinase-inactive missense mutations, unless otherwise compensated for, interfere with HR during embryogenesis.
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影响因子：
64.5
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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