Author: ["Peijing Zhang","Yongkun Wei","Li Wang","Bisrat G. Debeb","Yuan Yuan","Jinsong Zhang","Jingsong Yuan","Min Wang","Dahu Chen","Yutong Sun","Wendy A. Woodward","Yongqing Liu","Douglas C. Dean","Han Liang","Ye Hu","K. Kian Ang","Mien-Chie Hung","Junjie Chen","Li Ma"]
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Abstract
Epithelial–mesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance. However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties. Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response. Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of the kinase ATM and upregulation of ZEB1, and the latter promotes tumour cell radioresistance in vitro and in vivo. Mechanistically, ATM phosphorylates and stabilizes ZEB1 in response to DNA damage, ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitylate and stabilize CHK1, thereby promoting homologous recombination-dependent DNA repair and resistance to radiation. These findings identify ZEB1 as an ATM substrate linking ATM to CHK1 and the mechanism underlying the association between EMT and radioresistance. Ma and colleagues show that when the EMT-associated transcription factor ZEB1 is stabilized by the ATM kinase, it interacts with the ubiquitin protease USP7 to counteract CHK1 degradation and promote DNA repair in breast cancer cells.Cite this article
Zhang, P., Wei, Y., Wang, L. et al. ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1. Nat Cell Biol 16, 864–875 (2014). https://doi.org/10.1038/ncb3013 