Cancer-associated USP28 missense mutations disrupt 53BP1 interaction and p53 stabilization.

ABSTRACT: Cellular stress response pathways are essential for genome stability and are frequently dysregulated in cancer. Following mitotic stress, the ubiquitin-specific protease 28 (USP28) and the p53-binding protein 1 (53BP1) form a stable, heritable complex to stabilize the tumor suppressor p53, triggering cell cycle arrest or apoptosis. Here, we demonstrate that USP28 stabilizes p53 through deubiquitination. We further show that USP28 is required not only for an efficient stress response but also for maintaining basal p53 levels in some cancer cells. Loss of functional USP28 allows cells to evade mitotic stress and DNA damage responses in a manner that is specific to cell type and cancer context. We identify a prevalent, shorter USP28 isoform critical for p53 stabilization. Its C-terminal domai

SUBMITTER: Belal H 

PROVIDER: S-EPMC12689633 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature