Lee Hong-Jen, Lan Li, Peng Guang, Chang Wei-Chao, Hsu Ming-Chuan, Wang Ying-Nai, Cheng Chien-Chia, Wei Leizhen, Nakajima Satoshi, Chang Shih-Shin, Liao Hsin-Wei, Chen Chung-Hsuan, Lavin Martin, Ang K Kian, Lin Shiaw-Yih, Hung Mien-Chie
1] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [2] The University of Texas Graduate School of Biomedical Science at Houston, Houston, TX 77030, USA.
1] Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA [2] Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Cell Res. 2015 Feb;25(2):225-36. doi: 10.1038/cr.2015.8. Epub 2015 Jan 20.
Ataxia telangiectasia mutated (ATM) mediates DNA damage response by controling irradiation-induced foci formation, cell cycle checkpoint, and apoptosis. However, how upstream signaling regulates ATM is not completely understood. Here, we show that upon irradiation stimulation, ATM associates with and is phosphorylated by epidermal growth factor receptor (EGFR) at Tyr370 (Y370) at the site of DNA double-strand breaks. Depletion of endogenous EGFR impairs ATM-mediated foci formation, homologous recombination, and DNA repair. Moreover, pretreatment with an EGFR kinase inhibitor, gefitinib, blocks EGFR and ATM association, hinders CHK2 activation and subsequent foci formation, and increases radiosensitivity. Thus, we reveal a critical mechanism by which EGFR directly regulates ATM activation in DNA damage response, and our results suggest that the status of ATM Y370 phosphorylation has the potential to serve as a biomarker to stratify patients for either radiotherapy alone or in combination with EGFR inhibition.
共济失调毛细血管扩张症突变基因（ATM）通过控制辐射诱导的病灶形成、细胞周期检查点和细胞凋亡来介导DNA损伤反应。然而，上游信号如何调节ATM尚未完全明确。在此，我们表明在辐射刺激下，ATM在DNA双链断裂位点与表皮生长因子受体（EGFR）结合并在酪氨酸370（Y370）处被EGFR磷酸化。内源性EGFR的缺失会损害ATM介导的病灶形成、同源重组和DNA修复。此外，用EGFR激酶抑制剂吉非替尼预处理可阻断EGFR与ATM的结合，阻碍CHK2激活及随后的病灶形成，并增加放射敏感性。因此，我们揭示了一种关键机制，即EGFR在DNA损伤反应中直接调节ATM激活，我们的结果表明ATM Y370磷酸化状态有可能作为一种生物标志物，用于对单独放疗或联合EGFR抑制治疗的患者进行分层。
