1. Initiation of DNA replication requires actin dynamics and formin activity
- Author
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Nikolaos Parisis, Liliana Krasinska, Bethany Harker, James M. Dewar, Nathalie Morin, Daniel Fisher, Alain Camasses, Michel Rossignol, Serge Urbach, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut National de la Recherche Agronomique (INRA), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Vanderbilt University [Nashville], Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), ANR [ANR-09-BLAN-0252], Ligue Nationale Contre le Cancer, 'Equipe labellisee' [EL2010.LNCC/DF, EL2013.LNCC/DF], Region Languedoc Roussillon, and Canceropole GSO Mobility Grant [2016-M02]
- Subjects
0301 basic medicine ,Fetal Proteins ,Cytoplasm ,Transcription, Genetic ,Zygote ,Nuclear Localization Signals ,Xenopus ,Eukaryotic DNA replication ,Xenopus laevis ,0302 clinical medicine ,Nuclear protein ,ComputingMilieux_MISCELLANEOUS ,0303 health sciences ,biology ,General Neuroscience ,Microfilament Proteins ,Nuclear Proteins ,Articles ,Chromatin ,Cell biology ,medicine.anatomical_structure ,cyclin-dependent kinase ,Formins ,actin ,Signal Transduction ,DNA Replication ,formin ,Active Transport, Cell Nucleus ,nuclear transport ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,macromolecular substances ,Complex Mixtures ,Karyopherins ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Cell Line, Tumor ,Proliferating Cell Nuclear Antigen ,medicine ,Animals ,Humans ,Molecular Biology ,030304 developmental biology ,Cell Nucleus ,General Immunology and Microbiology ,DNA replication ,Epithelial Cells ,biology.organism_classification ,Actins ,Proliferating cell nuclear antigen ,Cell nucleus ,030104 developmental biology ,ran GTP-Binding Protein ,Gene Expression Regulation ,biology.protein ,Origin recognition complex ,MDia1 ,Nuclear transport ,030217 neurology & neurosurgery ,HeLa Cells - Abstract
Nuclear actin influences transcription in a manner dependent on its dynamics of polymerisation and nucleocytoplasmic translocation. Using human somatic cells and transcriptionally-silent Xenopus egg extracts, we show that actin dynamics is also required for DNA replication. We identify many actin regulators in replicating nuclei from Xenopus egg extracts, and show that in human cells, nuclear actin filaments form in early G1 and disassemble prior to S-phase. In either system, treatments that stabilise nuclear actin filaments abrogate nuclear transport and initiation of DNA replication. Mechanistically, actin directly binds RanGTP-importin complexes and disruption of its dynamics hinders cargo release. This prevents both nuclear pore complex (NPC) formation and active nuclear transport, which we show is required throughout DNA replication. Nuclear formin activity is required for two further steps: loading of cyclin-dependent kinase (CDK) and proliferating cell nuclear antigen (PCNA) onto chromatin and initiation of DNA replication. Thus, actin dynamics and formins are involved in several nuclear processes essential for cell proliferation.
- Published
- 2017