Journal
MOLECULAR CELL
Volume 71, Issue 4, Pages 510-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2018.06.025
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Funding
- Australian Cancer Research Foundation
- Australian Centre for Microscopy & Microanalysis at the University of Sydney
- Microbial Imaging Facility at the University of Technology Sydney
- University of New South Wales Biomedical Imaging Facility
- Cancer Council NSW [RG 16-09, RG 15-12]
- Australian Research Council [CE140100011, LP140100967, LE150100163]
- National Health and Medical Research Council of Australia [1059278, 1037320, 1053195, 1106241, 1104461]
- Cancer Institute NSW [11/FRL/5-02]
- National Health and Medical Research Council of Australia [1104461, 1106241] Funding Source: NHMRC
- Australian Research Council [LE150100163] Funding Source: Australian Research Council
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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.
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