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.
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Chii Shyang
authors.initials: CS
authors.lastname: Fong
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Gregory
authors.initials: G
authors.lastname: Mazo
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Tuhin
authors.initials: T
authors.lastname: Das
authors.affiliation: Oberlin College, Oberlin, United States.
authors.forename: Joshua
authors.initials: J
authors.lastname: Goodman
authors.affiliation: BCMB Graduate Program, Weill Cornell Medical School, New York, United States.
authors.forename: Minhee
authors.initials: M
authors.lastname: Kim
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
authors.forename: Brian P
authors.initials: BP
authors.lastname: O'Rourke
authors.affiliation: BCMB Graduate Program, Weill Cornell Medical School, New York, United States.
authors.forename: Denisse
authors.initials: D
authors.lastname: Izquierdo
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.|BCMB Graduate Program, Weill Cornell Medical School, New York, United States.
authors.forename: Meng-Fu Bryan
authors.identifier: 0000-0002-2159-8836
authors.initials: MF
authors.lastname: Tsou
mesh_terms: D059447:Cell Cycle Checkpoints; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D018390:Gene Targeting; D005820:Genetic Testing; D006801:Humans; D008938:Mitosis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C498301:TP53BP1 protein, human; D016159:Tumor Suppressor Protein p53; D000071857:Tumor Suppressor p53-Binding Protein 1; C442902:USP28 protein, human; D043222:Ubiquitin Thiolesterase
keywords: cell biology; cell cycle arrest; human; mitosis; stress signalling