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      Centrosomal Actin Assembly Is Required for Proper Mitotic Spindle Formation and Chromosome Congression

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          Summary

          Cytoskeletal cross talk between actin filaments and microtubules is a common mechanism governing the assembly of cellular structures, i.e., during filopodia formation or cilia organization. However, potential actin-microtubule interactions during mammalian cell divisions are less well understood. At mitotic entry, centrosomes propagate the formation of the mitotic spindle, thereby aligning individual chromosomes to the metaphase plate, a process coined chromosome congression. Here, we identify actin filament assembly spatially defined at centrosomes contemporaneously with spindle microtubules forming during prometaphase. We show that pharmacological Arp2/3 complex inhibition as well as overexpression of the Arp2/3 complex inhibitory protein Arpin decreased spindle actin. As a consequence, mitotic spindle formation is impaired, which resulted in disorganized chromosome congression and ultimately mitotic defects in non-transformed cells. Thus centrosomal Arp2/3 complex activity plays a role in the maintenance of genomic integrity during mitosis.

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          Highlights

          • •

            Spindle actin assembles upon prometaphase at centrosomes

          • •

            Spindle actin is branched and precedes kinetochore fibers

          • •

            Arp2/3 complex assembles spindle actin

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            Inhibition of Arp2/3 complex during mitotic entry impairs mitotic spindle formation

          Abstract

          Biological Sciences; Cell Biology; Organizational Aspects of Cell Biology; Functional Aspects of Cell Biology

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          Fluorogenic probes for live-cell imaging of the cytoskeleton.

          Gražvydas Lukinavičius, Luc Reymond, Elisa D'Este … (2014)
          We introduce far-red, fluorogenic probes that combine minimal cytotoxicity with excellent brightness and photostability for fluorescence imaging of actin and tubulin in living cells. Applied in stimulated emission depletion (STED) microscopy, they reveal the ninefold symmetry of the centrosome and the spatial organization of actin in the axon of cultured rat neurons with a resolution unprecedented for imaging cytoskeletal structures in living cells.
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            Identification and characterization of a small molecule inhibitor of formin-mediated actin assembly.

            Syed A. Rizvi, Erin Neidt, Jiayue Cui … (2009)
            Formins stimulate actin filament assembly for fundamental cellular processes including division, adhesion, establishing polarity, and motility. A formin inhibitor would be useful because most cells express multiple formins whose functions are not known and because metastatic tumor formation depends on the deregulation of formin-dependent processes. We identified a general small molecule inhibitor of formin homology 2 domains (SMIFH2) by screening compounds for the ability to prevent formin-mediated actin assembly in vitro. SMIFH2 targets formins from evolutionarily diverse organisms including yeast, nematode worm, and mice, with a half-maximal inhibitor concentration of approximately 5 to 15 microM. SMIFH2 prevents both formin nucleation and processive barbed end elongation and decreases formin's affinity for the barbed end. Furthermore, low micromolar concentrations of SMIFH2 disrupt formin-dependent, but not Arp2/3 complex-dependent, actin cytoskeletal structures in fission yeast and mammalian NIH 3T3 fibroblasts.
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              DNA damage induces nuclear actin filament assembly by Formin-2 and Spire-1/2 that promotes efficient DNA repair

              Brittany Belin, Terri Lee, R. Mullins (2015)
              Actin filaments assemble inside the nucleus in response to multiple cellular perturbations, including heat shock, protein misfolding, integrin engagement, and serum stimulation. We find that DNA damage also generates nuclear actin filaments—detectable by phalloidin and live-cell actin probes—with three characteristic morphologies: (i) long, nucleoplasmic filaments; (ii) short, nucleolus-associated filaments; and (iii) dense, nucleoplasmic clusters. This DNA damage-induced nuclear actin assembly requires two biologically and physically linked nucleation factors: Formin-2 and Spire-1/Spire-2. Formin-2 accumulates in the nucleus after DNA damage, and depletion of either Formin-2 or actin's nuclear import factor, importin-9, increases the number of DNA double-strand breaks (DSBs), linking nuclear actin filaments to efficient DSB clearance. Nuclear actin filaments are also required for nuclear oxidation induced by acute genotoxic stress. Our results reveal a previously unknown role for nuclear actin filaments in DNA repair and identify the molecular mechanisms creating these nuclear filaments. DOI: http://dx.doi.org/10.7554/eLife.07735.001
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                Author and article information

                Contributors
                Matthias Plessner
                Robert Grosse
                Journal
                Journal ID (nlm-ta): iScience
                Journal ID (iso-abbrev): iScience
                Title: iScience
                Publisher: Elsevier
                ISSN (Electronic): 2589-0042
                Publication date PMC-release: 28 April 2019
                Publication date Collection: 31 May 2019
                Publication date (Electronic): 28 April 2019
                Volume: 15
                Pages: 274-281
                Affiliations
                [1 ]Institute of Pharmacology, University of Freiburg, Albertstr. 25, 79104 Freiburg, Germany
                [2 ]CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Schänzlestr. 18, 79104 Freiburg, Germany
                Author notes
                [3]

                Lead Contact

                Article
                Publisher ID: S2589-0042(19)30119-1
                DOI: 10.1016/j.isci.2019.04.022
                PMC ID: 6520610
                PubMed ID: 31096079
                SO-VID: 7ac8e770-dbd6-43da-b7d9-ea0895934b3e
                Copyright © © 2019 The Author(s)
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 25 January 2019
                Date revision received : 29 March 2019
                Date accepted : 17 April 2019
                Categories
                Subject: Article

                Keywords: biological sciences,cell biology,organizational aspects of cell biology,functional aspects of cell biology
                Data availability:
                Keywords: biological sciences, cell biology, organizational aspects of cell biology, functional aspects of cell biology

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