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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly
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A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly

机译：TPP1和TIN2相互作用在高阶端粒复杂装配中的关键作用

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摘要

Mammalian telomeric proteins function through dynamic interactions with each other and telomere DNA. We previously reported the formation of a high-molecular-mass telomeric complex (the mammalian telosome) that contains the six core proteins TRF1, TRF2, RAP1, TIN2, POT1, and TPP1 (formerly named PTOP/PIP1/ TINT1) and mediates telomere end-capping and length control. In this report, we sought to elucidate the mechanism of six-protein complex (or shelterin) formation and the function of this complex. Through reconstitution experiments, we demonstrate here that TIN2 and TPP1 are key components in mediating the six-protein complex assembly. We demonstrate that not only TIN2 but also TPP1 are required to bridge the TRF1 and TRF2 subcomplexes. Specifically, TPP1 helps to stabilize the TRF1-TIN2-TRF2 interaction and promote six-protein complex formation. Consistent with this model, overexpression of TPP1 enhanced TIN2-TRF2 association. Conversely, knocking down TPP1 reduced the ability of endogenous TRF1 to associate with the TRF2 complex. Our results suggest that coordinated interactions among TPP1, TIN2, TRF1, and TRF2 may ensure robust assembly of the telosome, telomere targeting of its subunits, and, ultimately, regulated telomere maintenance.
机译：哺乳动物的端粒蛋白通过彼此和端粒DNA的动态相互作用而起作用。先前我们报道了包含六个核心蛋白TRF1，TRF2，RAP1，TIN2，POT1和TPP1（以前称为PTOP / PIP1 / TINT1）的高分子量端粒复合物（哺乳动物端粒）的形成，并介导端粒末端-封盖和长度控制。在本报告中，我们试图阐明六蛋白复合物（或庇护素）形成的机制以及该复合物的功能。通过重构实验，我们在这里证明TIN2和TPP1是介导六蛋白复合物装配的关键成分。我们证明，不仅需要TIN2，而且需要TPP1来桥接TRF1和TRF2子复合体。具体地说，TPP1有助于稳定TRF1-TIN2-TRF2相互作用并促进六蛋白复合物的形成。与该模型一致，TPP1的过表达增强了TIN2-TRF2关联。相反，敲除TPP1会降低内源TRF1与TRF2复合体缔合的能力。我们的结果表明，TPP1，TIN2，TRF1和TRF2之间的协调相互作用可以确保端粒的稳固装配，端粒靶向其亚基，并最终调节端粒的维持。

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