title: A USP28-53BP1-p53-p21 signaling axis arrests growth after centrosome loss or prolonged mitosis.
abstract: Precise regulation of centrosome number is critical for accurate chromosome segregation and the maintenance of genomic integrity. In nontransformed cells, centrosome loss triggers a p53-dependent surveillance pathway that protects against genome instability by blocking cell growth. However, the mechanism by which p53 is activated in response to centrosome loss remains unknown. Here, we have used genome-wide CRISPR/Cas9 knockout screens to identify a USP28-53BP1-p53-p21 signaling axis at the core of the centrosome surveillance pathway. We show that USP28 and 53BP1 act to stabilize p53 after centrosome loss and demonstrate this function to be independent of their previously characterized role in the DNA damage response. Surprisingly, the USP28-53BP1-p53-p21 signaling pathway is also required to arrest cell growth after a prolonged prometaphase. We therefore propose that centrosome loss or a prolonged mitosis activate a common signaling pathway that acts to prevent the growth of cells that have an increased propensity for mitotic errors.
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Bramwell G
authors.initials: BG
authors.lastname: Lambrus
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Vikas
authors.initials: V
authors.lastname: Daggubati
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655.
authors.forename: Yumi
authors.identifier: 0000-0003-3475-7936
authors.initials: Y
authors.lastname: Uetake
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Scott
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Clutario
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655.
authors.forename: Greenfield
authors.initials: G
authors.lastname: Sluder
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205 aholland@jhmi.edu.
authors.forename: Andrew J
authors.identifier: 0000-0003-3728-6367
authors.initials: AJ
authors.lastname: Holland
mesh_terms: D001483:Base Sequence; D064113:CRISPR-Cas Systems; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D049109:Cell Proliferation; D018385:Centrosome / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D055786:Gene Knockout Techniques; D006801:Humans; D008677:Metaphase; D008938:Mitosis; D055550:Protein Stability; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*
chemical_list: 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