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USP7 limits CDK1 activity throughout the cell cycle.

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USP7 inhibitors cause DNA damage and toxicity by activating CDK1, not just stabilizing P53. This unexpected CDK1 activation explains the genotoxicity of USP7 inhibitors.

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Cancer Research

Background:

  • USP7 inhibitors are explored as anticancer drugs by stabilizing P53.
  • USP7 inhibitors induce p53-independent DNA damage, but the mechanism is unclear.

Purpose of the Study:

  • Investigate the mechanism behind USP7 inhibitor-induced genotoxicity.
  • Determine the role of CDK1 and PP2A in USP7 inhibitor toxicity.

Main Methods:

  • Cell cycle analysis
  • Phosphoproteomic analysis
  • Inhibition and activation of USP7, PP2A, and CDK1

Main Results:

  • USP7 inhibition leads to widespread CDK1 activation and DNA damage, independent of P53.
  • USP7 interacts with and regulates the cytoplasmic localization of PP2A.
  • Inhibition of USP7 or PP2A causes similar phosphoproteome changes, including increased CDK1 target phosphorylation.
  • Reducing CDK1 activity or activating PP2A alleviates USP7 inhibitor toxicity.

Conclusions:

  • USP7 normally limits CDK1 activity throughout the cell cycle.
  • Untimely CDK1 activation by USP7 inhibitors causes DNA damage and cellular toxicity.
  • This provides a novel mechanism for the anticancer effects of USP7 inhibitors.