53BP1 and USP28 mediate p53-dependent cell cycle arrest in response to centrosome loss and prolonged mitosis

Elife. 2016 Jul 2:5:e16270. doi: 10.7554/eLife.16270.


Mitosis occurs efficiently, but when it is disturbed or delayed, p53-dependent cell death or senescence is often triggered after mitotic exit. To characterize this process, we conducted CRISPR-mediated loss-of-function screens using a cell-based assay in which mitosis is consistently disturbed by centrosome loss. We identified 53BP1 and USP28 as essential components acting upstream of p53, evoking p21-dependent cell cycle arrest in response not only to centrosome loss, but also to other distinct defects causing prolonged mitosis. Intriguingly, 53BP1 mediates p53 activation independently of its DNA repair activity, but requiring its interacting protein USP28 that can directly deubiquitinate p53 in vitro and ectopically stabilize p53 in vivo. Moreover, 53BP1 can transduce prolonged mitosis to cell cycle arrest independently of the spindle assembly checkpoint (SAC), suggesting that while SAC protects mitotic accuracy by slowing down mitosis, 53BP1 and USP28 function in parallel to select against disturbed or delayed mitosis, promoting mitotic efficiency.

Keywords: cell biology; cell cycle arrest; human; mitosis; stress signalling.

MeSH terms

  • Cell Cycle Checkpoints*
  • Cell Line
  • Centrosome / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Gene Targeting
  • Genetic Testing
  • Humans
  • Mitosis*
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor p53-Binding Protein 1 / metabolism*
  • Ubiquitin Thiolesterase / metabolism*


  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • TP53BP1 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor p53-Binding Protein 1
  • USP28 protein, human
  • Ubiquitin Thiolesterase