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


Authors: Fong, C. S.; Mazo, G.; Das, T.; Goodman, J.; Kim, M.; O'Rourke, B. P.; Izquierdo, D.; Tsou, M. F. B.
Article Title: 53BP1 and USP28 mediate p53-dependent cell cycle arrest in response to centrosome loss and prolonged mitosis
Abstract: 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: p53; centriole; heat-shock; tumor-suppressor; dna-damage checkpoint; mitotic arrest; spindle-assembly checkpoint; duplication; polo kinase; brct domains; requires
Journal Title: eLife
Volume: 5
ISSN: 2050-084X
Publisher: eLife Sciences Publications Ltd.  
Date Published: 2016-07-01
Start Page: e16270
Language: English
ACCESSION: WOS:000380859600001
DOI: 10.7554/eLite.16270
PROVIDER: wos
PMCID: PMC4946878
PUBMED: 27371829
Notes: Article -- Source: Wos
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MSK Authors
  1. Meng-Fu Bryan Tsou
    31 Tsou
  2. Chii Shyang Fong
    10 Fong
  3. Gregory   Mazo
    14 Mazo
  4. Tuhin   Das
    4 Das