A CPC-shelterin-BTR axis regulates mitotic telomere deprotection

Abstract

Telomeres prevent ATM activation by sequestering chromosome termini within telomere loops (t-loops). Mitotic arrest promotes telomere linearity and a localized ATM-dependent telomere DNA damage response (DDR) through an unknown mechanism. Using unbiased interactomics, biochemical screening, molecular biology, and super-resolution imaging, we found that mitotic arrest-dependent (MAD) telomere deprotection requires the combined activities of the Chromosome passenger complex (CPC) on shelterin, and the BLM-TOP3A-RMI1/2 (BTR) complex on t-loops. During mitotic arrest, the CPC component Aurora Kinase B (AURKB) phosphorylated both the TRF1 hinge and TRF2 basic domains. The former enhanced CPC and TRF1 interaction through the CPC Survivin subunit, while the latter promoted telomere linearity, telomere DDR activation dependent upon BTR double Holliday junction dissolution activity, and mitotic death. We identify that the TRF2 basic domain functions in mitosis-specific telomere protection and reveal TRF1 regulation over a physiological ATM-dependent telomere DDR. The data demonstrate that MAD telomere deprotection is a sophisticated active mechanism that exposes telomere ends to signal mitotic stress.