Superhelicity Constrains a Localized and R-Loop-Dependent Formation of G-Quadruplexes at the Upstream Region of Transcription,ACS Chemical Biology

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Superhelicity Constrains a Localized and R-Loop-Dependent Formation of G-Quadruplexes at the Upstream Region of Transcription
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-09-11 00:00:00 , DOI: 10.1021/acschembio.7b00435
Ke-wei Zheng ₁ , Yi-de He ₁ , Hong-he Liu ₁ , Xin-min Li ₁ , Yu-hua Hao ₁ , Zheng Tan ₁

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Transcription induces formation of intramolecular G-quadruplex structures at the upstream region of a DNA duplex by an upward transmission of negative supercoiling through the DNA. Currently the regulation of such G-quadruplex formation remains unclear. Using plasmid as a model, we demonstrate that while it is the dynamic negative supercoiling generated by a moving RNA polymerase that triggers a formation of a G-quadruplex, the constitutional superhelicity determines the potential and range of the formation of a G-quadruplex by constraining the propagation of the negative supercoiling. G-quadruplex formation is maximal in negatively supercoiled and nearly abolished in relaxed plasmids while being moderate in nicked and linear ones. The formation of a G-quadruplex strongly correlates with the presence of an R-loop. Preventing R-loop formation virtually abolished G-quadruplex formation even in the negatively supercoiled plasmid. Enzymatic action and protein binding that manipulate supercoiling or its propagation all impact the formation of G-quadruplexes. Because chromosomes and plasmids in cells in their natural form are maintained in a supercoiled state, our findings reveal a physical basis that justifies the formation and regulation of G-quadruplexes in vivo. The structural features involved in G-quadruplex formation may all serve as potential targets in clinical and therapeutic applications.

中文翻译：

超螺旋性限制了转录上游区域G-四链体的局部和R循环依赖性形成。

转录通过负超螺旋通过DNA的向上传递而诱导在DNA双链体的上游区域形成分子内G-四链体结构。目前，这种G-四链体形成的调控仍不清楚。使用质粒作为模型，我们证明，虽然由移动的RNA聚合酶产生的动态负超螺旋触发了G-四链体的形成，但构造超螺旋性通过限制G-四链体的形成潜力和范围负超螺旋的传播。在负超螺旋中，G-四链体的形成最大，而在松弛质粒中，G-四链体的形成几乎消失，而有切口的和线性的质粒中，G-四链体的形成适中。G-四链体的形成与R-环的存在密切相关。即使在负超螺旋质粒中，防止R环形成实际上也消除了G-四链体的形成。操纵超螺旋或其传播的酶促作用和蛋白质结合都会影响G-四链体的形成。由于细胞中的染色体和质粒以其天然形式保持超螺旋状态，因此我们的发现揭示了物理基础，可证明G-四链体的形成和调控体内。G-四链体形成所涉及的结构特征都可以作为临床和治疗应用中的潜在靶标。

更新日期：2017-09-11

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