School of Contemporary Sciences, University of Abertay, Kydd Building, 40 Bell street, Dundee DD1 1HG, UK.
Exp Biol Med (Maywood). 2012 Jun;237(6):622-34. doi: 10.1258/ebm.2012.011378. Epub 2012 Jun 22.
Ataxia-telangiectasia mutated (ATM) kinase is a component of a signalling mechanism that determines the process of decision-making in response to DNA damage and involves the participation of multiple proteins. ATM is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex, and orchestrates signalling cascades that initiate the DNA damage response. Cells lacking ATM are hypersensitive to insults, particularly genotoxic stress, induced through radiation or radiomimetic drugs. Here, we investigate the degree of ATM activation during time-dependent treatment with genotoxic agents and the effects of ATM on phospho-induction and localization of its downstream substrates. Additionally, we have demonstrated a new cell-cycle-independent mechanism of ATM gene regulation following ATM kinase inhibition with KU5593. Inhibition of ATM activity causes induction of ATM protein followed by oscillation and this mechanism is governed at the transcriptional level. Furthermore, this autoregulatory induction of ATM is also accompanied by a transient upregulation of p53, pATR and E2F1 levels. Since ATM inhibition is believed to sensitize cancer cells to genotoxic agents, this novel insight into the mechanism of ATM regulation might be useful for designing more precise strategies for modulation of ATM activity in cancer therapy.
共济失调毛细血管扩张突变（ATM）激酶是一种信号转导机制的组成部分，该机制决定了对 DNA 损伤的反应过程中的决策，并涉及多种蛋白质的参与。ATM 通过 Mre11-Rad50-Nbs1（MRN）DNA 修复复合物被 DNA 双链断裂（DSBs）激活，并协调启动 DNA 损伤反应的信号级联反应。缺乏 ATM 的细胞对刺激物，特别是通过辐射或放射模拟药物诱导的遗传毒性应激，高度敏感。在这里，我们研究了在与遗传毒性药物的时间依赖性处理过程中 ATM 的激活程度，以及 ATM 对其下游底物的磷酸化诱导和定位的影响。此外，我们已经证明了一种新的细胞周期非依赖性 ATM 基因调控机制，即在 ATM 激酶被 KU5593 抑制后。ATM 活性的抑制导致 ATM 蛋白的诱导，随后是振荡，这种机制受转录水平的控制。此外，这种 ATM 的自动诱导也伴随着 p53、pATR 和 E2F1 水平的短暂上调。由于 ATM 抑制被认为使癌细胞对遗传毒性药物敏感，因此，对 ATM 调节机制的这一新认识可能有助于设计更精确的策略来调节癌症治疗中的 ATM 活性。
