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首页> 美国卫生研究院文献>Molecules >Design and Properties of Ligand-Conjugated Guanine Oligonucleotides for Recovery of Mutated G-Quadruplexes
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Design and Properties of Ligand-Conjugated Guanine Oligonucleotides for Recovery of Mutated G-Quadruplexes

机译：配体结合的鸟嘌呤寡核苷酸的设计和性质用于回收突变的G-四链体。

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The formation of a guanine quadruplex DNA structure (G4) is known to repress the expression of certain cancer-related genes. Consequently, a mutated G4 sequence can affect quadruplex formation and induce cancer progression. In this study, we developed an oligonucleotide derivative consisting of a ligand-containing guanine tract that replaces the mutated G4 guanine tract at the promoter of the vascular endothelial growth factor (VEGF) gene. A ligand moiety consisting of three types of polyaromatic hydrocarbons, pyrene, anthracene, and perylene, was attached to either the 3′ or 5′ end of the guanine tract. Each of the ligand-conjugated guanine tracts, with the exception of anthracene derivatives, combined with other intact guanine tracts to form an intermolecular G4 on the mutated VEGF promoter. This intermolecular G4, exhibiting parallel topology and high thermal stability, enabled VEGF G4 formation to be recovered from the mutated sequence. Stability of the intramolecular G4 increased with the size of the conjugated ligand. However, suppression of intermolecular G4 replication was uniquely dependent on whether the ligand was attached to the 3′ or 5′ end of the guanine tract. These results indicate that binding to either the top or bottom guanine quartet affects unfolding kinetics due to polarization in DNA polymerase processivity. Our findings provide a novel strategy for recovering G4 formation in case of damage, and fine-tuning processes such as replication and transcription.
机译：已知鸟嘌呤四链体DNA结构（G4）的形成会抑制某些癌症相关基因的表达。因此，突变的G4序列可影响四链体形成并诱导癌症进展。在这项研究中，我们开发了一种寡核苷酸衍生物，该衍生物由含配体的鸟嘌呤束组成，该衍生物取代了血管内皮生长因子（VEGF）基因启动子处的突变G4鸟嘌呤束。由三种类型的多芳族烃，pyr，蒽和per组成的配体部分连接到鸟嘌呤束的3'或5'端。除蒽衍生物外，每个配体结合的鸟嘌呤束与其他完整的鸟嘌呤束结合以在突变的VEGF启动子上形成分子间G4。该分子间G4表现出平行的拓扑结构和高的热稳定性，使得能够从突变序列中恢复VEGF G4的形成。分子内G4的稳定性随缀合的配体的大小而增加。但是，分子间G4复制的抑制作用唯一取决于配体是连接在鸟嘌呤通道的3'端还是5'端。这些结果表明，由于DNA聚合酶持续合成过程中的极化作用，与顶部或底部鸟嘌呤四重奏结合会影响展开动力学。我们的发现提供了一种在受损的情况下恢复G4形成的新颖策略，以及微调过程（例如复制和转录）的方法。

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