生物
细胞周期
细胞生物学
DNA损伤
蛋白磷酸酶2
细胞周期蛋白依赖激酶1
磷酸化
DNA复制
磷酸酶
DNA再复制
有丝分裂
细胞周期检查点
细胞周期蛋白依赖激酶
生物化学
细胞生长
泛素
染色质
细胞周期进展
分子生物学
作者
Antonio Galarreta,Pablo Valledor,Patricia Ubieto-Capella,Vanesa Lafarga,Eduardo Zarzuela,Javier Munoz,Marcos Malumbres,Emilio Lecona,Oscar Fernandez-Capetillo
标识
DOI:10.15252/embj.201899692
摘要
Chemical inhibitors of the deubiquitinase USP7 are currently being developed as anticancer agents based on their capacity to stabilize P53. Regardless of this activity, USP7 inhibitors also generate DNA damage in a p53-independent manner. However, the mechanism of this genotoxicity and its contribution to the anticancer effects of USP7 inhibitors are still under debate. Here we show that, surprisingly, even if USP7 inhibitors stop DNA replication, they also induce a widespread activation of CDK1 throughout the cell cycle, which leads to DNA damage and is toxic for mammalian cells. In addition, USP7 interacts with the phosphatase PP2A and supports its active localization in the cytoplasm. Accordingly, inhibition of USP7 or PP2A triggers very similar changes of the phosphoproteome, including a widespread increase in the phosphorylation of CDK1 targets. Importantly, the toxicity of USP7 inhibitors is alleviated by lowering CDK1 activity or by chemical activation of PP2A. Our work reveals that USP7 limits CDK1 activity at all cell cycle stages, providing a novel mechanism that explains the toxicity of USP7 inhibitors through untimely activation of CDK1.
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