Nuclear factor erythroid 2-related factor 2 (NRF2) is a well-characterized transcription factor that protects cells against oxidative and electrophilic stresses. Emerging evidence has suggested that NRF2 protects cells against DNA damage by mechanisms other than antioxidation, yet the mechanism remains poorly understood. Here, we demonstrate that knockout of NRF2 in cells results in hypersensitivity to ionizing radiation (IR) in the presence or absence of reactive oxygen species (ROS). Under ROS scavenging conditions, induction of DNA double-strand breaks (DSBs) increases the NRF2 protein level and recruits NRF2 to DNA damage sites where it interacts with ATR, resulting in activation of the ATR–CHK1–CDC2 signaling pathway. In turn, this leads to G2 cell cycle arrest and the promotion of homologous recombination repair of DSBs, thereby preserving genome stability. The inhibition of NRF2 by brusatol increased the radiosensitivity of tumor cells in xenografts by perturbing ATR and CHK1 activation. Collectively, our results reveal a novel function of NRF2 as an ATR activator in the regulation of the cellular response to DSBs. This shift in perspective should help furnish a more complete understanding of the function of NRF2 and the DNA damage response.

中文翻译：

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NRF2 通过促进 ATR 激活和 G2 细胞周期停滞来保持基因组完整性。

核因子红细胞 2 相关因子 2 (NRF2) 是一种特征明确的转录因子，可保护细胞免受氧化和亲电应激。新出现的证据表明，NRF2 通过抗氧化以外的机制保护细胞免受 DNA 损伤，但其机制仍知之甚少。在这里，我们证明，在存在或不存在活性氧（ROS）的情况下，细胞中 NRF2 的敲除会导致对电离辐射（IR）过敏。在 ROS 清除条件下，DNA 双链断裂 (DSB) 的诱导会增加 NRF2 蛋白水平，并将 NRF2 招募到 DNA 损伤位点，与 ATR 相互作用，从而激活 ATR-CHK1-CDC2 信号通路。反过来，这会导致 G2 细胞周期停滞并促进 DSB 的同源重组修复，从而保持基因组稳定性。brusatol 对 NRF2 的抑制通过扰乱 ATR 和 CHK1 的激活来增加异种移植物中肿瘤细胞的放射敏感性。总的来说，我们的结果揭示了 NRF2 作为 ATR 激活剂在调节细胞对 DSB 反应中的新功能。这种观点的转变应该有助于更全面地了解 NRF2 的功能和 DNA 损伤反应。