USP7 limits CDK1 activity throughout the cell cycle.

Autor: Galarreta, Antonio, Valledor, Pablo, Ubieto‐Capella, Patricia, Lafarga, Vanesa, Zarzuela, Eduardo, Muñoz, Javier, Malumbres, Marcos, Lecona, Emilio, Fernandez‐Capetillo, Oscar
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Zdroj: EMBO Journal; Jun2021, Vol. 40 Issue 11, p1-13, 13p
Abstrakt: 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. SYNOPSIS: Inhibitors of the USP7 deubiquitinase are being developed as anticancer agents due to their capacity to stabilize p53. Here, the finding that USP7 suppresses CDK1 activity throughout the cell cycle, this leading to DNA damage in replicating cells, reveals a novel mechanism of USP7 inhibitor toxicity. USP7 inhibition leads to a widespread increase in CDK1 activity throughout the cell cycle.USP7 interacts with PP2A and is required for maintenance of PP2A cytoplasmic localization.Inhibition of USP7 or PP2A triggers similar changes in the phosphoproteome.The toxicity of USP7 inhibitors is mitigated by chemicals that inhibit CDK1 or activate PP2A. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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