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|Title:||Telomere loop dynamics in chromosome end protection|
|Author:||Van Ly, D.|
|Citation:||Molecular Cell, 2018; 71(4):510-525|
|David Van Ly, Ronnie Ren Jie Low, Sonja Frölich, Tara K.Bartolec, Georgia R.Kafer, Hilda A.Pickett, Katharina Gaus, Anthony J.Cesare|
|Abstract:||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.|
|Keywords:||ATM; Aurora B kinase; DNA damage response; TRF2; mitosis; non-homologous end joining; super-resolution microscopy; telomere loops; telomere protection; telomeres|
|Rights:||© 2018 Elsevier Inc.|
|Appears in Collections:||Genetics publications|
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