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

Authors: Benarroch-Popivker, Delphine; Pisano, Sabrina; Mendez-Bermudez, Aaron; Lototska, Liudmyla; Kaur, Parminder; Bauwens, Serge; Djerbi, Nadir; Latrick, Chrysa M; Fraisier, Vincent; Pei, Bei; Gay, Alexandre; Jaune, Emilie; Foucher, Kevin; Cherfils-Vicini, Julien; Aeby, Eric; Miron, Simona; Londoño-Vallejo, Arturo; Ye, Jing; Le Du, Marie-Hélène; Wang, Hong; Gilson, Eric; Giraud-Panis, Marie-Josèphe

Published In Mol Cell, (2016 Jan 21)

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.

PubMed ID: 26774283

MeSH Terms: Ataxia Telangiectasia Mutated Proteins/metabolism; Base Pairing; DNA Damage; DNA End-Joining Repair; DNA/chemistry*; DNA/metabolism; HeLa Cells; Humans; Lysine/metabolism; Models, Molecular; Mutation; Nucleic Acid Conformation*; Protein Structure, Tertiary; Shelterin Complex; Signal Transduction; Telomere-Binding Proteins/metabolism; Telomere/metabolism*; Telomeric Repeat Binding Protein 2/chemistry; Telomeric Repeat Binding Protein 2/metabolism*