Related Experiment Video

Updated: Nov 6, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

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Restraining CDK1-cyclin B activation: PP2A on the cUSP(7)

Marilynn Chow-Castro1, Shandee D Dixon1, Joshua C Saldivar1,2

  • 1Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.

The EMBO Journal
|May 10, 2021
PubMed

Insights

USP7 inhibitors, used to stabilize p53, cause unexpected toxicity by disrupting cell cycle regulation. This study reveals USP7 inhibition causes PP2A redistribution and CDK1-dependent phosphorylation, impacting genomic integrity.

Area of Science:

  • Molecular biology
  • Cell biology
  • Cancer therapeutics

Background:

  • USP7 inhibitors are investigated for cancer therapy by stabilizing p53 via MDM2 degradation.
  • These inhibitors exhibit p53-independent toxicity through an uncharacterized mechanism.

Purpose of the Study:

  • To elucidate the mechanism behind p53-independent toxicity induced by USP7 inhibitors.
  • To identify the role of USP7 inhibition in cellular regulation and its impact on genomic integrity.

Main Methods:

  • Cellular and molecular biology techniques were employed.
  • Analysis of protein localization, phosphorylation events, and cell cycle progression.

Main Results:

  • USP7 inhibition causes a shift of Protein Phosphatase 2A (PP2A) from the cytoplasm to the nucleus.
  • Increased CDK1-dependent phosphorylation occurs throughout the cell cycle upon USP7 inhibition.
  • This leads to aberrant progression of S-phase cells into mitosis, compromising genomic integrity.

Conclusions:

  • USP7 inhibition triggers a novel toxicity pathway involving PP2A redistribution and aberrant cell cycle control.
  • Understanding this mechanism is crucial for developing safer USP7-targeting cancer therapies.
  • The findings reveal a new regulatory pathway for cell cycle progression and genomic stability.

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