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首页> 外文学位 >Investigation on the Secondary Structures Formed in Full-length Telomere Overhang and Rational Design of Ligands for Targeting Telomere G-quadruplexes.
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Investigation on the Secondary Structures Formed in Full-length Telomere Overhang and Rational Design of Ligands for Targeting Telomere G-quadruplexes.

机译：靶向端粒G-四链体的全长端粒悬突中形成的二级结构和配体的合理设计研究。

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摘要

The 3′ human telomeric overhang provides ample opportunities for the formation and interaction of G-quadruplexes, which have shown impacts on many biological functions including telomerase activities in the telomere region. However, in the few investigations on DNA sequences that approach to the full length of the human telomeric overhang, the presence of higher order quadruplex-quadruplex interactions is still a subject of debate. As a part of this dissertation, an enzymatic dynamic splint ligation (DSL) strategy was developed to prepare a DNA construct of 24G-tracts and longer, which has the length comparable to the full stretch of 3' human telomeric overhang. Using mechanical unfolding assays in laser tweezers, we observed a minor population (~5%) of higher order interactions between G-quadruplexes while the majority of the quadruplexes follow the beads-on-a-string model. Analyses on the non-interacting G-quadruplexes in the 24G construct showed features similar to those of the stand-alone G-quadruplexes in the 5'-(TTAGGG) 4 (4G) construct. As each 24G construct contains as many as six G-quadruplexes, this method offers increased throughput for the time-consuming mechanical unfolding experiments of non-B DNA structures.;Targeting DNA G-quadruplexes using small-molecule ligands has shown to modulate biological functions mediated by G-quadruplexes inside cells. Given >716,000 G-quadruplex hosting sites in the human genome, the specific binding of ligands to quadruplex becomes problematic. Here, a polyvalency based mechanism was innovated to target multiple telomeric G-quadruplexes specifically. A tetrameric telomestatin derivative was evaluated for its complex polyvalent binding with multiple G-quadruplexes by single-molecule mechanical unfolding in laser tweezers. We found a derivative of telomestatin (L2H2-6OTD) tetramer binds to multimeric telomeric G-quadruplexes 40 times stronger than monomeric quadruplexes, which can be ascribed to the polyvalency induced unstacking of binding units (or PIU binding) for G-quadruplexes. While stacking of telomestatin units in the tetramer imparts steric hindrance for the ligand to access standalone G-quadruplexes, the stacking disassembles to accommodate the potent polyvalent binding between the tetramer ligand and multimeric G-quadruplexes. This adaptive PIU binding offers a generic mechanism to target polymeric biomolecules prevalent inside cells selectively.
机译：3'人端粒突出端为G-四链体的形成和相互作用提供了充足的机会，这已显示出对许多生物学功能（包括端粒区域中的端粒酶活性）的影响。然而，在对接近人类端粒突出端全长的DNA序列的研究中，高阶四链体-四链体相互作用的存在仍然是一个争论的话题。作为本论文的一部分，开发了一种酶促动态夹板连接（DSL）策略来制备24G片段及更长的DNA构建体，其长度可与3'人端粒突出端的全长相媲美。在激光镊子中使用机械展开试验，我们观察到少数群体（〜5％）的G-四链体之间的高阶相互作用，而大多数的四链体遵循串珠模型。对24G构建体中非相互作用的G-四链体的分析显示出与5'-（TTAGGG）4（4G）构建体中独立G-四链体相似的特征。由于每个24G构建体最多包含六个G-四链体，因此该方法为非B DNA结构的费时的机械展开实验提供了更高的通量。;使用小分子配体靶向DNA G-四链体已显示出调节生物功能的作用。由细胞内的G-四链体介导。鉴于人类基因组中有超过716,000个G-四链体宿主位点，配体与四链体的特异性结合变得成问题。在这里，创新了一种基于多价的机制，专门针对多个端粒G-四链体。通过激光镊子中的单分子机械展开，评估了四聚体telomestatin衍生物与多个G-四链体的复杂多价结合。我们发现端粒他汀类药物（L2H2-6OTD）四聚体与多聚端粒G-四链体的结合比单体四联体强40倍，这可以归因于多价诱导的G-四链体结合单元的解叠（或PIU结合）。在四聚体中端粒他汀类单元的堆叠为配体进入独立的G-四链体提供了空间位阻，而堆叠则解体以适应四聚体配体与多聚体G-四链体之间的有效多价结合。这种自适应性PIU结合提供了一种通用机制，可选择性地靶向细胞内普遍存在的聚合物分子。

著录项

  • 作者

    Abraham Punnoose, Jibin.;

  • 作者单位

    Kent State University.;

  • 授予单位 Kent State University.;
  • 学科 Molecular biology.;Chemistry.;Biochemistry.
  • 学位 Ph.D.
  • 年度 2018
  • 页码 121 p.
  • 总页数 121
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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