Format

Send to

Choose Destination
Mol Cell. 2016 Jan 21;61(2):274-86. doi: 10.1016/j.molcel.2015.12.009. Epub 2016 Jan 7.

TRF2-Mediated Control of Telomere DNA Topology as a Mechanism for Chromosome-End Protection.

Author information

1
Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, CNRS UMR7284, INSERM U1081, University of Nice Sophia Antipolis, Nice, France.
2
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.
3
Physics Department, North Carolina State University at Raleigh, Raleigh, NC 27695, USA.
4
Cell and Tissue Imaging Platform (PICT-IBiSA), Nikon Imaging Centre, UMR 144 CNRS Institut Curie, 75248 Paris Cedex 05, France.
5
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
6
Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Bâtiment 144, CEA Saclay, Gif-sur-Yvette F-91191, France.
7
UMR3244, Telomeres and Cancer Laboratory, Institut Curie, Paris 75248, France.
8
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.
9
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.
10
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.

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.

KEYWORDS:

DNA topology; DNA wrapping; RAP1; TRF2; telomere

PMID:
26774283
PMCID:
PMC5001171
DOI:
10.1016/j.molcel.2015.12.009
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center