爪蟾
秀丽隐杆线虫
生物
细胞生物学
DNA损伤
Notch信号通路
调节器
信号转导
DNA
遗传学
基因
作者
Jelena Vermezovic,Marek Adamowicz,Libero Santarpia,Alessandra Rustighi,Mattia Forcato,Caterina Lucano,Lucia Massimiliano,Vincenzo Costanzo,Silvio Bicciato,Giannino Del Sal,Fabrizio d’Adda di Fagagna
摘要
Assays in both C. elegans and human cells show that Notch interacts with ATM kinase to inhibit the DNA-damage response and that Notch activity is inversely correlated with ATM activation in breast cancer cells. The DNA-damage response (DDR) ensures genome stability and proper inheritance of genetic information, both of which are essential to survival. It is presently unclear to what extent other signaling pathways modulate DDR function. Here we show that Notch receptor binds and inactivates ATM kinase and that this mechanism is evolutionarily conserved in Caenorhabditis elegans, Xenopus laevis and humans. In C. elegans, the Notch pathway impairs DDR signaling in gonad germ cells. In mammalian cells, activation of human Notch1 leads to reduced ATM signaling in a manner independent of Notch1 transcriptional activity. Notch1 binds directly to the regulatory FATC domain of ATM and inhibits ATM kinase activity. Notch1 and ATM activation are inversely correlated in human breast cancers, and inactivation of ATM by Notch1 contributes to the survival of Notch1-driven leukemia cells upon DNA damage.
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