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Telomere Maintenance through Spatial Control of Telomeric Proteins

机译：通过端粒蛋白的空间控制来维持端粒

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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, TPP1 contains a functional nuclear export signal that directly controls the amount of TPP1 and POT1 in the nucleus. Furthermore, binding of TIN2 to TPP1 promotes the nuclear localization of TPP1 and POT1. We also found that disrupting TPP1 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.
机译：六个人类端粒蛋白TRF1，TRF2，RAP1，TIN2，POT1和TPP1可以形成称为端粒/ shelterin的复合物，这是端粒保护和长度控制所必需的。已显示TPP1通过与TIN2结合来调节POT1端粒的定位和端粒组装。此类相互作用在何处发生以及端粒蛋白的细胞区隔对于端粒的维持是否重要尚待确定。我们在这里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相互定位并相互作用。出乎意料的是，TPP1包含一个功能性的核输出信号，该信号直接控制核中TPP1和POT1的数量。此外，TIN2与TPP1的结合会促进TPP1和POT1的核定位。我们还发现破坏TPP1核输出可能导致端粒DNA损伤反应和端粒长度失调。我们的发现突显了细胞质中TIN2，TPP1和POT1之间的协同相互作用如何调节细胞核中端粒的装配和功能，并首次表明了核输出和端粒蛋白空间控制在端粒维持中的重要性。

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