Telomere Loop Dynamics in Chromosome End Protection

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.