Romero-Zamora Diana, Rogers Samuel, Low Ronnie Ren Jie, Page Scott G, Lane Blake J E, Kosaka Shunya, Robinson Andrew B, French Lucy, Lamm Noa, Ishikawa Fuyuki, Hayashi Makoto T, Cesare Anthony J
Graduate School of Biostudies, Kyoto University, Sakyo, Kyoto, Japan.
IFOM-KU Joint Research Laboratory, Graduate School of Medicine, Kyoto University, Sakyo, Kyoto, Japan.
Nat Commun. 2025 Mar 17;16(1):2277. doi: 10.1038/s41467-025-57456-8.
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. Phosphorylation of the TRF1 hinge domain enhances CPC and TRF1 interaction through the CPC Survivin subunit. Meanwhile, phosphorylation of the TRF2 basic domain promotes telomere linearity, activates a telomere DDR dependent on BTR-mediated double Holliday junction dissolution, and leads to mitotic death. We identify that the TRF2 basic domain functions in mitosis-specific telomere protection and reveal a regulatory role for TRF1 in controlling 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.
端粒通过将染色体末端隔离在端粒环（t环）中来防止ATM激活。有丝分裂停滞通过未知机制促进端粒线性化和局部依赖ATM的端粒DNA损伤反应（DDR）。利用无偏向性相互作用组学、生化筛选、分子生物学和超分辨率成像技术，我们发现有丝分裂停滞依赖性（MAD）端粒去保护需要染色体乘客复合体（CPC）在庇护蛋白上以及BLM-TOP3A-RMI1/2（BTR）复合体在t环上的联合作用。在有丝分裂停滞期间，CPC组分极光激酶B（AURKB）使TRF1铰链区和TRF2碱性结构域磷酸化。TRF1铰链区的磷酸化通过CPC存活蛋白亚基增强CPC与TRF1的相互作用。同时，TRF2碱性结构域的磷酸化促进端粒线性化，激活依赖于BTR介导的双Holliday连接溶解的端粒DDR，并导致有丝分裂死亡。我们确定TRF2碱性结构域在有丝分裂特异性端粒保护中起作用，并揭示了TRF1在控制生理性依赖ATM的端粒DDR中的调节作用。数据表明，MAD端粒去保护是一种复杂的主动机制，可使端粒末端暴露以信号有丝分裂应激。
