Promotion of DNA repair by nuclear IKKβ phosphorylation of ATM in response to genotoxic stimuli.
Promotion of DNA repair by nuclear IKKβ phosphorylation of ATM in response to genotoxic stimuli.
复制标题
响应基因毒性刺激，ATM 的核 IKKβ 磷酸化促进 DNA 修复。
作者：
Kei Sakamoto;et al.
共济失调毛细血管扩张突变 (ATM) 是参与细胞对 DNA 损伤反应的关键分子之一。激活的 ATM 的一部分从细胞核输出到细胞质，在细胞质中激活 I kappa B 激酶/核因子 kappa B (IKK/NF-κB) 信号通路。人们认为，活化的 IKKβ 是 NF-κB 激活的关键激酶，通常存在于细胞质中，并磷酸化细胞质下游分子，例如 IκBα。在这里，我们确定了 IKKβ 在 DNA 损伤响应过程中的新作用。烷化剂引起的 ATM 磷酸化由两个阶段组成：早期阶段（最多 3 小时）和晚期阶段（6 小时后）。发现 DNA 损伤反应过程中产生的一部分活化的 IKKβ 易位到细胞核中，并在后期直接磷酸化 ATM。此外，ATM 被核 IKKβ 磷酸化可以促进 DNA 修复。与此同时，激活的 IKKβ 诱导经典的 NF-κB 激活并参与抗凋亡。我们的研究结果定义了 IKKβ 在 DNA 损伤反应过程中的功能，促进细胞存活和 DNA 修复，并维持细胞稳态。
Ataxia-telangiectasia mutated (ATM) is one of the key molecules involved in the cellular response to DNA damage. A portion of activated ATM is exported from the nucleus into the cytoplasm, where it activates the I kappa B kinase/nuclear factor kappa B (IKK/NF-κB) signaling pathway. It has been thought that activated IKKβ, which is a critical kinase for NF-κB activation, generally resides in the cytoplasm and phosphorylates cytoplasmic downstream molecules, such as IκBα. Here, we identified a new role for IKKβ during the response to DNA damage. ATM phosphorylation in response to alkylating agents consisted of two phases: the early phase (up to 3 h) and late phase (after 6 h). A portion of the activated IKKβ generated during the DNA damage response was found to translocate into the nucleus and directly phosphorylate ATM in the late phase. Furthermore, the phosphorylation of ATM by nuclear IKKβ was suggested to promote DNA repair. In parallel, activated IKKβ induced classical NF-κB activation and was involved in anti-apoptosis. Our findings define the function of IKKβ during the response to DNA damage, which promotes cell survival and DNA repair, and maintains cellular homeostasis.