期刊
MOLECULAR CELL
卷 71, 期 4, 页码 510-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2018.06.025
关键词
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资金
- 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
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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