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Telomere Loop Dynamics in Chromosome End Protection

Molecular cell, 2018-08, Vol.71 (4), p.510-525.e6 [Peer Reviewed Journal]

2018 Elsevier Inc. ;Copyright © 2018 Elsevier Inc. All rights reserved. ;ISSN: 1097-2765 ;EISSN: 1097-4164 ;DOI: 10.1016/j.molcel.2018.06.025 ;PMID: 30033372

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  • Title:
    Telomere Loop Dynamics in Chromosome End Protection
  • Author: Van Ly, David ; Low, Ronnie Ren Jie ; Frölich, Sonja ; Bartolec, Tara K. ; Kafer, Georgia R. ; Pickett, Hilda A. ; Gaus, Katharina ; Cesare, Anthony J.
  • Subjects: ATM ; Aurora B kinase ; DNA damage response ; mitosis ; non-homologous end joining ; super-resolution microscopy ; telomere loops ; telomere protection ; telomeres ; TRF2
  • Is Part Of: Molecular cell, 2018-08, Vol.71 (4), p.510-525.e6
  • Description: Telomeres regulate DNA damage response (DDR) and DNA repair activity at chromosome ends. How telomere macromolecular structure contributes to ATM regulation and its potential dissociation from control over non-homologous end joining (NHEJ)-dependent telomere fusion is of central importance to telomere-dependent cell aging and tumor suppression. Using super-resolution microscopy, we identify that ATM activation at mammalian telomeres with reduced TRF2 or at human telomeres during mitotic arrest occurs specifically with a structural change from telomere loops (t-loops) to linearized telomeres. Additionally, we find the TRFH domain of TRF2 regulates t-loop formation while suppressing ATM activity. Notably, we demonstrate that ATM activation and telomere linearity occur separately from telomere fusion via NHEJ and that linear DDR-positive telomeres can remain resistant to fusion, even during an extended G1 arrest, when NHEJ is most active. Collectively, these results suggest t-loops act as conformational switches that specifically regulate ATM activation independent of telomere mechanisms to inhibit NHEJ. [Display omitted] •The TRFH domain of TRF2 regulates t-loop formation•ATM is suppressed at chromosome ends when telomeres are in a t-loop conformation•ATM is activated when telomeres are linearized by altered TRF2 or mitotic arrest•Linearized DDR-positive telomeres can remain NHEJ resistant even during G1 arrest Van Ly et al. identify that telomere loops (t-loops) function as conformational switches that regulate ATM activity at chromosome ends. They find ATM activity is suppressed when telomeres adopt a t-loop conformation and that ATM is activated with linearized chromosome ends.
  • Publisher: United States: Elsevier Inc
  • Language: English
  • Identifier: ISSN: 1097-2765
    EISSN: 1097-4164
    DOI: 10.1016/j.molcel.2018.06.025
    PMID: 30033372
  • Source: Cell Press Free Archives
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