Abstract
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.