Telomere maintenance through spatial control of telomeric proteins
Telomere maintenance through spatial control of telomeric proteins
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DOI：
10.1128/mcb.00603-07
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发表时间：
2007-08-01
影响因子：
5.3
通讯作者：
Zhou Songyang
中科院分区：
文献类型：
--
作者：
Chen, Liuh-Yow;Liu, Dan;Zhou Songyang
6种人类端粒蛋白TRF1、TRF2、RAP1、TIN2、POT1和TPP1可以形成一种称为端粒/保护素的复合体，这是端粒保护和长度控制所必需的。TPP1已被证明通过与TIN2结合来调节POT1端粒定位和端粒组装。这种相互作用发生在哪里，以及端粒蛋白的细胞区隔对端粒维持是否重要，仍有待确定。在这里，我们系统地研究了人类端粒蛋白的细胞定位和相互作用。有趣的是，我们发现TIN2、TPP1和POT1在细胞质和细胞核中都定位并相互作用。出乎意料的是，TPPI含有一个功能性核输出信号，直接控制核内TPPI和POT1的量。此外，TIN2与TPP1的结合促进了TPP1和POT1的核定位。我们还发现，干扰TPPI核出口可以导致端粒DNA损伤反应和端粒长度失调。我们的发现突出了细胞质中TIN2、TPP1和POT1之间的协调相互作用如何调节核内端粒的组装和功能，并首次表明核输出和端粒蛋白的空间控制在端粒维持中的重要性。
The six human telomeric proteins TRF1, TRF2, RAP1, TIN2, POT1, and TPP1 can form a complex called the telosome/shelterin, which is required for telomere protection and length control. TPP1 has been shown to regulate both POT1 telomere localization and telosome assembly through its binding to TIN2. It remains to be determined where such interactions take place and whether cellular compartmentalization of telomeric proteins is important for telomere maintenance. We systematically investigated here the cellular localization and interactions of human telomeric proteins. Interestingly, we found TIN2, TPP1, and POT1 to localize and interact with each other in both the cytoplasm and the nucleus. Unexpectedly, TPPI contains a functional nuclear export signal that directly controls the amount of TPPI and POT1 in the nucleus. Furthermore, binding of TIN2 to TPP1 promotes the nuclear localization of TPP1 and POT1. We also found that disrupting TPPI nuclear export could result in telomeric DNA damage response and telomere length disregulation. Our findings highlight how the coordinated interactions between TIN2, TPP1, and POT1 in the cytoplasm regulate the assembly and function of the telosome in the nucleus and indicate for the first time the importance of nuclear export and spatial control of telomeric proteins in telomere maintenance.