Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer.
Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer.
复制标题
对人类癌症中 POT1-TPP1 相互作用和 POT1 C 末端突变的结构见解。
DOI：
10.1038/ncomms14929
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发表时间：
2017-04-10
影响因子：
16.6
通讯作者：
Lei M
中科院分区：
文献类型：
--
作者：
Chen C;Gu P;Wu J;Chen X;Niu S;Sun H;Wu L;Li N;Peng J;Shi S;Fan C;Huang M;Wong CC;Gong Q;Kumar-Sinha C;Zhang R;Pusztai L;Rai R;Chang S;Lei M
哺乳动物庇护蛋白POT 1和TPP 1形成稳定的异源二聚体，保护染色体末端并调节端粒聚合酶介导的端粒延伸。然而，POT 1如何与TPP 1相互作用仍然未知。在这里，我们提出的晶体结构的C-末端部分的人POT 1（POT 1C）与POT 1结合基序的TPP 1复合。结构表明POT 1C包含两个结构域，第三个OB折叠和一个Holliday连接消退酶样结构域。这两个结构域对于结合TPP 1是必需的。值得注意的是，与纤毛原生动物Oxytricha novaTEBPα-β复合物的心形结构不同，POT 1-TPP 1采用细长的V形构象。此外，我们在人类癌症中发现了几个错义突变，这些突变破坏了POT 1C-TPP 1相互作用，导致POT 1不稳定。结合TPP 1的POT 1C突变体定位于端粒，但不能抑制DNA损伤反应和A-NHEJ的不适当修复。我们的研究结果表明，POT 1 C端是必不可少的，以防止启动基因组不稳定性允许肿瘤发生。
Mammalian shelterin proteins POT1 and TPP1 form a stable heterodimer that protects chromosome ends and regulates telomerase-mediated telomere extension. However, how POT1 interacts with TPP1 remains unknown. Here we present the crystal structure of the C-terminal portion of human POT1 (POT1C) complexed with the POT1-binding motif of TPP1. The structure shows that POT1C contains two domains, a third OB fold and a Holliday junction resolvase-like domain. Both domains are essential for binding to TPP1. Notably, unlike the heart-shaped structure of ciliated protozoanOxytricha novaTEBPα–β complex, POT1–TPP1 adopts an elongated V-shaped conformation. In addition, we identify several missense mutations in human cancers that disrupt the POT1C–TPP1 interaction, resulting in POT1 instability. POT1C mutants that bind TPP1 localize to telomeres but fail to repress a DNA damage response and inappropriate repair by A-NHEJ. Our results reveal that POT1 C terminus is essential to prevent initiation of genome instability permissive for tumorigenesis.