title: TRF2-Mediated Control of Telomere DNA Topology as a Mechanism for Chromosome-End Protection.
abstract: The shelterin proteins protect telomeres against activation of the DNA damage checkpoints and recombinational repair. We show here that a dimer of the shelterin subunit TRF2 wraps ∼ 90 bp of DNA through several lysine and arginine residues localized around its homodimerization domain. The expression of a wrapping-deficient TRF2 mutant, named Top-less, alters telomeric DNA topology, decreases the number of terminal loops (t-loops), and triggers the ATM checkpoint, while still protecting telomeres against non-homologous end joining (NHEJ). In Top-less cells, the protection against NHEJ is alleviated if the expression of the TRF2-interacting protein RAP1 is reduced. We conclude that a distinctive topological state of telomeric DNA, controlled by the TRF2-dependent DNA wrapping and linked to t-loop formation, inhibits both ATM activation and NHEJ. The presence of RAP1 at telomeres appears as a backup mechanism to prevent NHEJ when topology-mediated telomere protection is impaired.
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Benarroch-Popivker
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pisano
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France; International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital/CNRS/INSERM/Nice University, Pôle Sino-Français de Recherche en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital, Huangpu, Shanghai 200025, P.R. China.
authors.forename: Aaron
authors.initials: A
authors.lastname: Mendez-Bermudez
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Liudmyla
authors.initials: L
authors.lastname: Lototska
authors.affiliation: Physics Department, North Carolina State University at Raleigh, Raleigh, NC 27695, USA.
authors.forename: Parminder
authors.initials: P
authors.lastname: Kaur
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Bauwens
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Nadir
authors.initials: N
authors.lastname: Djerbi
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Chrysa M
authors.initials: CM
authors.lastname: Latrick
authors.affiliation: Cell and Tissue Imaging Platform (PICT-IBiSA), Nikon Imaging Centre, UMR 144 CNRS Institut Curie, 75248 Paris Cedex 05, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Fraisier
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Bei
authors.initials: B
authors.lastname: Pei
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Gay
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Jaune
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Foucher
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Cherfils-Vicini
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Aeby
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Bâtiment 144, CEA Saclay, Gif-sur-Yvette F-91191, France.
authors.forename: Simona
authors.initials: S
authors.lastname: Miron
authors.affiliation: UMR3244, Telomeres and Cancer Laboratory, Institut Curie, Paris 75248, France.
authors.forename: Arturo
authors.initials: A
authors.lastname: Londoño-Vallejo
authors.affiliation: International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital/CNRS/INSERM/Nice University, Pôle Sino-Français de Recherche en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital, Huangpu, Shanghai 200025, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ye
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Bâtiment 144, CEA Saclay, Gif-sur-Yvette F-91191, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Le Du
authors.affiliation: Physics Department, North Carolina State University at Raleigh, Raleigh, NC 27695, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France; International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital/CNRS/INSERM/Nice University, Pôle Sino-Français de Recherche en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital, Huangpu, Shanghai 200025, P.R. China; Department of Genetics, CHU Nice, Nice 06202, France. Electronic address: eric.gilson@unice.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.affiliation: Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France. Electronic address: giraud-panis@unice.fr.
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Giraud-Panis
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D020029:Base Pairing; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004249:DNA Damage; D059766:DNA End-Joining Repair; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D009690:Nucleic Acid Conformation; D017434:Protein Structure, Tertiary; D000089804:Shelterin Complex; D015398:Signal Transduction; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; D004247:DNA; D064007:Ataxia Telangiectasia Mutated Proteins; D008239:Lysine
keywords: DNA topology; DNA wrapping; RAP1; TRF2; telomere