MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
Science. 2022 Mar 11;375(6585):1173-1176. doi: 10.1126/science.abn6840. Epub 2022 Feb 24.
Telomerase maintains genome stability by extending the 3' telomeric repeats at eukaryotic chromosome ends, thereby counterbalancing progressive loss caused by incomplete genome replication. In mammals, telomerase recruitment to telomeres is mediated by TPP1, which assembles as a heterodimer with POT1. We report structures of DNA-bound telomerase in complex with TPP1 and with TPP1-POT1 at 3.2- and 3.9-angstrom resolution, respectively. Our structures define interactions between telomerase and TPP1-POT1 that are crucial for telomerase recruitment to telomeres. The presence of TPP1-POT1 stabilizes the DNA, revealing an unexpected path by which DNA exits the telomerase active site and a DNA anchor site on telomerase that is important for telomerase processivity. Our findings rationalize extensive prior genetic and biochemical findings and provide a framework for future mechanistic work on telomerase regulation.
端粒酶通过延伸真核染色体末端的 3' 端粒重复序列来维持基因组稳定性，从而抵消不完全基因组复制所导致的渐进性丢失。在哺乳动物中，端粒酶被 TPP1 募集到端粒，TPP1 与 POT1 形成异二聚体。我们报告了 DNA 结合的端粒酶与 TPP1 以及 TPP1-POT1 复合物的结构，分辨率分别为 3.2 和 3.9 埃。我们的结构定义了端粒酶与 TPP1-POT1 之间的相互作用，这些相互作用对于端粒酶招募到端粒至关重要。TPP1-POT1 的存在稳定了 DNA，揭示了一个出人意料的 DNA 离开端粒酶活性位点的途径，以及一个对端粒酶进程性很重要的 DNA 锚定位点。我们的发现合理化了广泛的先前遗传和生化发现，并为端粒酶调节的未来机制工作提供了框架。
