CTC1 OB-B interaction with TPP1 terminates telomerase and prevents telomere overextension.
CTC1 OB-B interaction with TPP1 terminates telomerase and prevents telomere overextension.
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DOI：
10.1093/nar/gkad237
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发表时间：
2023-06-09
影响因子：
14.9
通讯作者：
中科院分区：
文献类型：
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CST（CTC 1-STN 1-TEN 1）是一种端粒相关复合物，可与ssDNA结合，是端粒复制中多个步骤所必需的，包括端粒酶终止G链延伸和合成互补C链。CST包含7个OB折叠，它们似乎通过调节CST与ssDNA的结合以及CST招募或接合伴侣蛋白的能力来介导CST功能。然而，科技委履行其各种职能的机制仍不清楚。为了解决这一机制，我们产生了一系列CTC 1突变体，并研究了它们对CST与ssDNA结合的影响以及它们在CTC 1 −/−细胞中拯救CST功能的能力。我们确定OB-B结构域是端粒酶终止的关键决定因素，而不是C链合成。CTC 1-ΔB的表达挽救了C链的填充，防止了端粒DNA损伤信号传导和生长停滞。然而，它导致端粒进行性延长和端粒酶在端粒的积累，表明无法限制端粒酶的作用。CTC 1-ΔB突变大大降低了CST-TPP 1相互作用，但仅适度影响ssDNA结合。OB-B点突变也削弱了TPP 1的相关性，TPP 1相互作用的缺陷跟踪无法限制端粒酶作用。总之，我们的研究结果表明，CTC 1-TPP 1相互作用在端粒酶终止中起着关键作用。
CST (CTC1-STN1-TEN1) is a telomere associated complex that binds ssDNA and is required for multiple steps in telomere replication, including termination of G-strand extension by telomerase and synthesis of the complementary C-strand. CST contains seven OB-folds which appear to mediate CST function by modulating CST binding to ssDNA and the ability of CST to recruit or engage partner proteins. However, the mechanism whereby CST achieves its various functions remains unclear. To address the mechanism, we generated a series of CTC1 mutants and studied their effect on CST binding to ssDNA and their ability to rescue CST function in CTC1−/− cells. We identified the OB-B domain as a key determinant of telomerase termination but not C-strand synthesis. CTC1-ΔB expression rescued C-strand fill-in, prevented telomeric DNA damage signaling and growth arrest. However, it caused progressive telomere elongation and the accumulation of telomerase at telomeres, indicating an inability to limit telomerase action. The CTC1-ΔB mutation greatly reduced CST-TPP1 interaction but only modestly affected ssDNA binding. OB-B point mutations also weakened TPP1 association, with the deficiency in TPP1 interaction tracking with an inability to limit telomerase action. Overall, our results indicate that CTC1-TPP1 interaction plays a key role in telomerase termination.
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