ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1.
ATM-mediated stabilization of ZEB1 promotes DNA damage response and radioresistance through CHK1.
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DOI：
10.1038/ncb3013
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发表时间：
2014-09
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
--
作者：
上皮-间质转化（EMT）与乳腺癌干细胞的特性相关，包括化疗耐药性和放射耐药性。然而，目前还不清楚是否EMT本身或特定的EMT监管机构在这些属性中发挥因果作用。在这里，我们确定了EMT诱导转录因子，锌指E-box结合同源框1（ZEB 1），作为辐射敏感性和DNA损伤反应（DDR）的调节剂。来自电离辐射的乳腺癌细胞的辐射抗性亚群表现出ATM的超活化和ZEB 1的上调，并且ZEB 1在体外和体内促进肿瘤细胞的辐射抗性。从机制上讲，ATM激酶磷酸化并稳定ZEB 1以响应DNA损伤，ZEB 1反过来直接与USP 7相互作用并增强其去泛素化和稳定CHK 1的能力，从而促进同源重组依赖性DNA修复和对辐射的抗性。这些发现确定ZEB 1作为ATM底物连接ATM和CHK 1，并作为EMT和辐射抗性之间的关联的机制。
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 (DDR). Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of ATM and upregulation of ZEB1, and ZEB1 promotes tumor cell radioresistance in vitro and in vivo. Mechanistically, ATM kinase phosphorylates and stabilizes ZEB1 in response to DNA damage, and ZEB1 in turn directly interacts with USP7 and enhances its ability to deubiquitinate 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 as the mechanism underlying the association between EMT and radioresistance.
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影响因子：
11.2
作者：
Leung-Pineda V;Huh J;Piwnica-Worms H
通讯作者：
Piwnica-Worms H
USP7抵消了SCFBETATATRCP-，但不反对APCCDH1介导的链蛋白蛋白水解。
DOI：
10.1083/jcb.200807137
发表时间：
2009-01-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Faustrup H;Bekker-Jensen S;Bartek J;Lukas J;Mailand N
通讯作者：
Mailand N
影响因子：
56.9
作者：
Cortez, D;Wang, Y;Elledge, SJ
通讯作者：
Elledge, SJ
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
21.3
作者：
Collis, Spencer J.;Barber, Louise J.;Boulton, Simon J.
通讯作者：
Boulton, Simon J.