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首页> 外文期刊>Journal of Molecular Biology >POT1-TPP1 Binding and Unfolding of Telomere DNA Discriminates against Structural Polymorphism
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POT1-TPP1 Binding and Unfolding of Telomere DNA Discriminates against Structural Polymorphism

机译：Pot1-TPP1端粒DNA的结合和展开抑制结构多态性

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摘要

Telomeres are nucleoprotein complexes that reside at the ends of linear chromosomes and help maintain genomic integrity. Protection of telomeres 1 (POT1) and TPP1 are telomere-specific proteins that bind as a heterodimer to single-stranded telomere DNA to prevent illicit DNA damage responses and to enhance telomerase-mediated telomere extension. Telomere DNA is guanosine rich and, as such, can form highly stable secondary structures including G-quadruplexes. G-quadruplex DNA folds into different topologies that are determined by several factors including monovalent ion composition and the precise sequence and length of the DNA. Here, we explore the influence of DNA secondary structure on POT1-TPP1 binding. Equilibrium binding assays reveal that the POT1-TPP1 complex binds G-quadruplex structures formed in buffers containing Na+ with an affinity that is fivefold higher than for G-quadruplex structures formed in the presence of K+. However, the binding of the second heterodimer is insensitive to DNA secondary structure, presumably due to unfolding resulting from binding of the first POT1-TPP1. We further show that the rate constant for POT1-TPP1-induced unfolding of DNA secondary structure is substantially faster for G-quadruplex topologies formed in the presence of Na+ ions. When bound to DNA, POT1-TPP1 forms complexes with similar CD spectra and enhances telomerase activity for all DNA substrates tested, regardless of the substrate secondary structure or solution monovalent ion composition. Together, these data indicate that binding of POT1-TPP1 unfolds telomere secondary structure to assist loading of additional heterodimers and to ensure efficient promotion of telomerase-mediated extension. (C) 2016 Elsevier Ltd. All rights reserved.
机译：端粒是核蛋白复合物，其位于线性染色体的末端并有助于保持基因组完整性。端粒体1（POT1）和TPP1的保护是端粒特异性蛋白质，其与单链端粒DNA的异二聚体结合，以防止非法DNA损伤反应并增强端粒酶介导的端粒延伸。端粒DNA是富含鸟氨酸富含的，因此可以形成高度稳定的二次结构，包括G-四翻转。 G-Quadruplex DNA折叠成不同的拓扑，其由包括单价离子组成的几个因子和DNA的精确序列和长度决定。在这里，我们探讨DNA二级结构对Pot1-TPP1结合的影响。平衡结合测定揭示Pot1-TPP1复合物结合在含有Na +的缓冲液中形成的G-Quadwlex结构，其亲和力比在k +存在下形成的G-Quadwlex结构的五倍。然而，第二异二聚体的结合对DNA二级结构不敏感，可能是由于第一POT1-TPP1的结合所得到的展开。我们进一步表明，在Na +离子存在下形成的G-Quadreplex拓扑结构的Pot1-TPP1诱导的Pot1-TPP1诱导展开的速率常数基本上更快。当与DNA的DNA结合时，POT1-TPP1与具有相似CD光谱的复合物形成复合物，并增强所有测试的所有DNA基材的端粒酶活性，无论基材二级结构还是溶液一价离子组合物。这些数据在一起表明Pot1-TPP1的结合展开了端粒二次结构，以帮助加载额外的异二聚体，并确保有效促进端粒酶介导的延伸。 （c）2016 Elsevier有限公司保留所有权利。

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