Nuclear ataxia-telangiectasia mutated (ATM) mediates the cellular response to DNA double strand breaks in human neuron-like cells
Nuclear ataxia-telangiectasia mutated (ATM) mediates the cellular response to DNA double strand breaks in human neuron-like cells
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DOI：
10.1074/jbc.m601895200
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发表时间：
2006-06-23
影响因子：
4.8
通讯作者：
Shiloh, Yosef
中科院分区：
文献类型：
--
作者：
Biton, Sharon;Dar, Inbal;Shiloh, Yosef
蛋白激酶ATM（共济失调-毛细血管扩张突变）激活细胞对双链断裂（DSB）的反应，这是一种高度细胞毒性的DNA损伤。ATM被DSB激活，反过来磷酸化许多损伤反应途径中的关键参与者。ATM在常染色体隐性遗传疾病共济失调-毛细血管扩张症（A-T）中缺失或失活，其特征在于神经元变性、免疫缺陷、基因组不稳定性、辐射敏感性和癌症易感性。A-T的主要症状是由于小脑皮质和周围神经病变的持续变性导致的运动协调性的进行性丧失。理解A-T的一个主要缺陷是缺乏关于ATM在神经元中作用的信息。目前还不清楚ATM介导的DSB反应是否在这些细胞中类似于增殖细胞。此外，据报道，ATM在神经元中是细胞质的，并建议在这些细胞中的能力，而不是DNA损伤反应。近年来，我们获得了遗传分子证据，证明A-T的神经元变性是由DNA损伤反应缺陷引起的。因此，我们进行了调查，在一个模型系统中的人神经元样细胞（NLC）的神经元分化培养获得的这种反应。ATM在NLC中主要是核，并且它们对DSB的ATM介导的反应与增殖细胞的那些相似。敲除ATM不干扰神经元分化，但取消ATM介导的损伤反应在NLC。我们的结论是，核ATM介导的DSB反应在NLC中类似于在增殖细胞。试图了解A-T中的神经变性，应该直接研究神经系统中的DSB反应。
The protein kinase ATM (ataxia-telangiectasia mutated) activates the cellular response to double strand breaks (DSBs), a highly cytotoxic DNA lesion. ATM is activated by DSBs and in turn phosphorylates key players in numerous damage response pathways. ATM is missing or inactivated in the autosomal recessive disorder ataxia-telangiectasia (A-T), which is characterized by neuronal degeneration, immunodeficiency, genomic instability, radiation sensitivity, and cancer predisposition. The predominant symptom of A-T is a progressive loss of movement coordination due to ongoing degeneration of the cerebellar cortex and peripheral neuropathy. A major deficiency in understanding A-T is the lack of information on the role of ATM in neurons. It is unclear whether the ATM-mediated DSB response operates in these cells similarly to proliferating cells. Furthermore, ATM was reported to be cytoplasmic in neurons and suggested to function in these cells in capacities other than the DNA damage response. Recently we obtained genetic molecular evidence that the neuronal degeneration in A-T does result from defective DNA damage response. We therefore undertook to investigate this response in a model system of human neuron-like cells (NLCs) obtained by neuronal differentiation in culture. ATM was largely nuclear in NLCs, and their ATM-mediated responses to DSBs were similar to those of proliferating cells. Knocking down ATM did not interfere with neuronal differentiation but abolished ATM-mediated damage responses in NLCs. We concluded that nuclear ATM mediates the DSB response in NLCs similarly to in proliferating cells. Attempts to understand the neurodegeneration in A-T should be directed to investigating the DSB response in the nervous system.