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USP7 counteracts the activation of the mitotic program

ABSTRACT: Chemical inhibitors of the deubiquitinase USP7 are currently being developed as anticancer agents, due to their capacity to activate P53. Regardless of this activity, USP7 inhibitors also generate DNA damage in a p53-independent manner. However, the mechanism of this genotoxicity remains unknown. Surprisingly, even if USP7 inhibitors stop DNA replication, this occurs concomitant to a premature activation of mitotic kinases such as CDK1, which impairs chromosome segregation and is toxic for mammalian cells. Mechanistically, we show that USP7 interacts with the phosphatase PP2A and regulates its function. Accordingly, USP7 or PP2A inhibition trigger similar changes on the phosphoproteome, with a particular bias towards mitotic targets. Supporting our model, the toxicity of USP7 inhibitors is alleviated by lowering CDK1 activity or by the chemical activation of PP2A. Our work sheds light into the mechanism of action of USP7 inhibitors and provides the first example of triggering premature mitotic entry through perturbation of ubiquitin signaling.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Retinal Pigment Epithelial Cell, Cell Culture

SUBMITTER: Eduardo Zarzuela

LAB HEAD: Javier Muñoz

PROVIDER: PXD016623 | Pride | 2021-03-09

REPOSITORIES: Pride

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	20180918_EZ_Galarret_TMT_Tio2_Vial2_F2.raw	Raw
	20180919_EZ_Galarret_TMT_Tio2_Vial2_F1.raw	Raw
	20180919_EZ_Galarret_TMT_Tio2_Vial2_F3.raw	Raw
	20180919_EZ_Galarret_TMT_Tio2_Vial2_F4.raw	Raw
	20180919_EZ_Galarret_TMT_Tio2_Vial2_F5.raw	Raw

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