Blog
About
Search
Advanced search

7
views
26
references
 Top references
42
cited by
 Most cited
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      0
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      A USP28–53BP1–p53–p21 signaling axis arrests growth after centrosome loss or prolonged mitosis

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Lambrus et al. show that centrosome loss or a prolonged mitosis activates a USP28–53BP1–p53–p21 signaling axis that prevents the growth of cells with an increased propensity for mitotic errors.

          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.

          Related collections

          Most cited references 26

          • Record: found
          • Abstract: found
          • Article: not found

          RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins.

           Carsten Doil,  Jiri Bartek,  Claudia Lukas … (2009)
          DNA double-strand breaks (DSBs) not only interrupt the genetic information, but also disrupt the chromatin structure, and both impairments require repair mechanisms to ensure genome integrity. We showed previously that RNF8-mediated chromatin ubiquitylation protects genome integrity by promoting the accumulation of repair factors at DSBs. Here, we provide evidence that, while RNF8 is necessary to trigger the DSB-associated ubiquitylations, it is not sufficient to sustain conjugated ubiquitin in this compartment. We identified RNF168 as a novel chromatin-associated ubiquitin ligase with an ability to bind ubiquitin. We show that RNF168 interacts with ubiquitylated H2A, assembles at DSBs in an RNF8-dependent manner, and, by targeting H2A and H2AX, amplifies local concentration of lysine 63-linked ubiquitin conjugates to the threshold required for retention of 53BP1 and BRCA1. Thus, RNF168 defines a new pathway involving sequential ubiquitylations on damaged chromosomes and uncovers a functional cooperation between E3 ligases in genome maintenance.
          Article 0 comments Cited 224 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Genome-wide CRISPR screen in a mouse model of tumor growth and metastasis.

             Sidi Chen,  Neville E. Sanjana,  Kaijie Zheng … (2015)
            Genetic screens are powerful tools for identifying genes responsible for diverse phenotypes. Here we describe a genome-wide CRISPR/Cas9-mediated loss-of-function screen in tumor growth and metastasis. We mutagenized a non-metastatic mouse cancer cell line using a genome-scale library with 67,405 single-guide RNAs (sgRNAs). The mutant cell pool rapidly generates metastases when transplanted into immunocompromised mice. Enriched sgRNAs in lung metastases and late-stage primary tumors were found to target a small set of genes, suggesting that specific loss-of-function mutations drive tumor growth and metastasis. Individual sgRNAs and a small pool of 624 sgRNAs targeting the top-scoring genes from the primary screen dramatically accelerate metastasis. In all of these experiments, the effect of mutations on primary tumor growth positively correlates with the development of metastases. Our study demonstrates Cas9-based screening as a robust method to systematically assay gene phenotypes in cancer evolution in vivo.
            Article 0 comments Cited 214 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Enhanced phosphorylation of p53 by ATM in response to DNA damage.

               S Banin,  Y. Ziv,  Blair Anderson … (1998)
              The ATM protein, encoded by the gene responsible for the human genetic disorder ataxia telangiectasia (A-T), regulates several cellular responses to DNA breaks. ATM shares a phosphoinositide 3-kinase-related domain with several proteins, some of them protein kinases. A wortmannin-sensitive protein kinase activity was associated with endogenous or recombinant ATM and was abolished by structural ATM mutations. In vitro substrates included the translation repressor PHAS-I and the p53 protein. ATM phosphorylated p53 in vitro on a single residue, serine-15, which is phosphorylated in vivo in response to DNA damage. This activity was markedly enhanced within minutes after treatment of cells with a radiomimetic drug; the total amount of ATM remained unchanged. Various damage-induced responses may be activated by enhancement of the protein kinase activity of ATM.
              Article 0 comments Cited 203 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-ta): J Cell Biol
                Journal ID (iso-abbrev): J. Cell Biol
                Journal ID (publisher-id): jcb
                Journal ID (hwp): jcb
                Title: The Journal of Cell Biology
                Publisher: The Rockefeller University Press
                ISSN (Print): 0021-9525
                ISSN (Electronic): 1540-8140
                Publication date (Print): 18 July 2016
                Volume: 214
                Issue: 2
                Pages: 143-153
                Affiliations
                [1 ]Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205
                [2 ]Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655
                Author notes
                Correspondence to Andrew J. Holland: aholland@ 123456jhmi.edu
                [*]

                B.G. Lambrus and V. Daggubati contributed equally to this paper.

                Article
                Publisher ID: 201604054
                DOI: 10.1083/jcb.201604054
                PMC ID: 4949452
                PubMed ID: 27432896
                Copyright statement: © 2016 Lambrus et al.
                License:

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                Product
                Funding
                Funded by: March of Dimes http://dx.doi.org/10.13039/100000912
                Funded by: National Institutes of Health http://dx.doi.org/10.13039/100000002
                Funded by: GM 114119
                Funded by: GM 30758
                Categories
                Subject: Research Articles
                Subject: Report

                Data availability:

                ScienceOpen disciplines: Cell biology

                Comments

                Comment on this article