多胺结合对 DNA i-motif 结构稳定性的影响,ACS Omega

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多胺结合对 DNA i-motif 结构稳定性的影响
ACS Omega ( IF 3.7 ) Pub Date : 2019-05-22 00:00:00 , DOI: 10.1021/acsomega.9b00784
Michael M Molnar ₁ , Shelby C Liddell ₁ , Randy M Wadkins ₁

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B型DNA在超螺旋胁迫等条件下可以采用替代结构。当互补 DNA 链上鸟苷和胞嘧啶不对称分布时，可选择替代 DNA 结构。富含鸟苷的链可以形成称为四链体 (G4) 的四链结构。互补的富含胞嘧啶的链可以利用插入的胞嘧啶-胞嘧啶碱基配对形成称为 i 基序 (iM) 的四链结构。这两种二级结构都是从双链 DNA (dsDNA) 开始向上爬升的，这意味着它们的形成需要额外的因素。大多数 iM 需要弱酸性条件来稳定结构。然而，诸如聚乙二醇和葡聚糖之类的拥挤剂可以将iM 的 pKa 改变至接近生理学的 pH 值 ≈ 7。长期以来，人们就知道核酸可以被多胺（如腐胺、亚精胺和精胺）结合和稳定_。多胺在细胞中的浓度非常高 (0.1–30 mM)，它们与 DNA 的结合是由静电相互作用驱动的。多胺通常结合在 DNA 小沟中。然而，由于 iMs 的特殊结构，尚不清楚多胺是否也可以结合并稳定 iMs。这里描述的研究是为了分析多胺-iM 相互作用。iM 结构的热稳定性和 pH 依赖性是在多胺存在下测定的。与 dsDNA 相比，我们的结果表明多胺与 iM 的相互作用要弱得多，iM pH 依赖性和热稳定性变化最小就证明了这一点。我们的结果表明，多胺不太可能提供体内 iM 稳定的重要来源。

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Effects of Polyamine Binding on the Stability of DNA i-Motif Structures

B-form DNA can adopt alternative structures under conditions such as superhelical duress. Alternative DNA structures are favored when there is asymmetric distribution of guanosine and cytosine on complimentary DNA strands. A guanosine-rich strand can form a four-stranded structure known as a quadruplex (G4). The complimentary cytosine-rich strand can utilize intercalating cytosine–cytosine base pairing to form a four-stranded structure known as the i-motif (iM). Both secondary structures are energetically uphill from double-strand DNA (dsDNA), meaning that additional factors are needed for their formation. Most iMs require slightly acidic conditions for structure stabilization. However, crowding agents such as polyethylene glycols and dextrans can shift the pK_a of the iM to near-physiological pH ≈ 7. Nucleic acids have long been known to be bound and stabilized by polyamines such as putrescine, spermidine, and spermine. Polyamines have very high concentrations in cells (0.1–30 mM), and their binding to DNA is driven by electrostatic interactions. Polyamines typically bind in the minor groove of DNA. However, because of the unusual structure of iMs, it was unknown whether polyamines might also bind and stabilize iMs. The study described here was undertaken to analyze polyamine–iM interactions. The thermal stability and pH dependence of iM structures were determined in the presence of polyamines. In contrast to dsDNA, our results suggest that polyamines have considerably weaker interactions with iMs, as demonstrated by the minimal change in iM pH dependence and thermal stability. Our results suggest that polyamines are unlikely to provide a significant source of iM stabilization in vivo.

更新日期：2019-05-22

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