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

USP7 inhibitors are gaining momentum as a therapeutic strategy to stabilize p53 through their ability to induce MDM2 degradation. However, these inhibitors come with an unexpected p53-independent toxicity, via an unknown mechanism. In this issue of The EMBO Journal, Galarreta et al report how inhibition of USP7 leads to re-distribution of PP2A from cytoplasm to nucleus and an increase of deleterious CDK1-dependent phosphorylation throughout the cell cycle, revealing a new regulatory mechanism for the progression of S-phase cells toward mitosis to maintain genomic integrity.

Automated summary

USP7 inhibitors are gaining traction as a therapeutic strategy for stabilizing p53, but they also come with unexpected p53-independent toxicity through an unknown mechanism. New research shows that inhibition of USP7 leads to the redistribution of PP2A from the cytoplasm to the nucleus, and an increase in deleterious CDK1-dependent phosphorylation throughout the cell cycle, revealing a new regulatory mechanism for maintaining genomic integrity in S-phase cells progressing towards mitosis.