Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.
CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
Structure. 2022 Dec 1;30(12):1565-1572.e4. doi: 10.1016/j.str.2022.10.004.
Telomerase is crucial for telomere maintenance and genome integrity. The most salient feature of Tetrahymena telomerase is that its CST subcomplex (p75-p45-p19) is tethered to the telomerase catalytic core by interacting with the hub p50. Although the cryoelectron microscopy (cryo-EM) structures of Tetrahymena telomerase have recently been reported, the mechanisms of how and why p50 bridges the CST subcomplex to the telomerase catalytic core remain unclear. Here, we present the nuclear magnetic resonance (NMR) structure of the p75-p50 complex. Loss of the interaction between p75 and p50 detaches the CST subcomplex from the telomerase catalytic core in Tetrahymena. The tethering of the CST subcomplex to telomerase is required for telomere homeostasis. However, the detached CST subcomplex is still capable of facilitating the telomeric complementary-strand (C-strand) fill in similar to the non-tethered CST complexes in other organisms. These results expand our understanding of telomere synthesis in Tetrahymena.
端粒酶对于端粒维持和基因组完整性至关重要。四膜虫端粒酶最显著的特征是其 CST 亚基（p75-p45-p19）通过与中心 p50 相互作用而被连接到端粒酶催化核心。尽管最近已经报道了四膜虫端粒酶的低温电子显微镜（cryo-EM）结构，但 p50 如何以及为何将 CST 亚基桥接到端粒酶催化核心的机制仍不清楚。在这里，我们展示了 p75-p50 复合物的核磁共振（NMR）结构。p75 与 p50 之间的相互作用丧失会导致 CST 亚基从四膜虫中的端粒酶催化核心上脱离。CST 亚基与端粒酶的连接对于端粒稳态是必需的。然而，即使 CST 亚基脱离，它仍然能够促进类似于其他生物体中非连接的 CST 复合物的端粒互补链（C 链）填充。这些结果扩展了我们对四膜虫中端粒合成的理解。
