2′-Fluoroarabinonucleic acid modification traps G-quadruplex and i-motif structures in human telomeric DNA
2′-Fluoroarabinonucleic acid modification traps G-quadruplex and i-motif structures in human telomeric DNA
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DOI：
10.1093/nar/gkx838
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发表时间：
2017-11-16
影响因子：
14.9
通讯作者：
Damha, Masad J.
中科院分区：
文献类型：
--
作者：
Assi, Hala Abou;El-Khoury, Roberto;Damha, Masad J.
人类端粒和基因启动子区域在细胞衰老和癌症中发挥着重要作用。这些区域由富含鸟嘌呤和胞嘧啶的重复序列组成，在某些条件下可以分别折叠成 G-四链体 (G4) 和 i-基序结构。在此，我们使用紫外、圆二色性和核磁共振光谱来研究几种人类端粒序列，并证明 G4/i-基序-双链体互变动力学因 2'-β-氟化和 G4/i-基序-双链体连接的存在而显着减慢。对天然和修饰的富含 C 和 G 的人类端粒序列的 1:1 混合物进行的 NMR 监测动力学实验表明，链杂交动力学受 G4 或 i 基序展开控制。此外，我们还提供了 NMR 证据，证明在中性 pH 条件下形成了含有 G4 和 i-motif 结构的混合复合物，该复合物邻近双链 DNA 片段。虽然 i 基序和 G4 折叠的存在在启动子基因组序列中可能是相互排斥的，但我们的结果表明它们可能作为端粒序列中的中间体短暂共存。
Human telomeres and promoter regions of genes fulfill a significant role in cellular aging and cancer. These regions comprise of guanine and cytosine-rich repeats, which under certain conditions can fold into G-quadruplex (G4) and i-motif structures, respectively. Herein, we use UV, circular dichroism and NMR spectroscopy to study several human telomeric sequences and demonstrate that G4/i-motif-duplex interconversion kinetics are slowed down dramatically by 2'-beta-fluorination and the presence of G4/i-motif-duplex junctions. NMR-monitored kinetic experiments on 1:1 mixtures of native and modified C- and G-rich human telomeric sequences reveal that strand hybridization kinetics are controlled by G4 or i-motif unfolding. Furthermore, we provide NMR evidence for the formation of a hybrid complex containing G4 and i-motif structures proximal to a duplex DNA segment at neutral pH. While the presence of i-motif and G4 folds may be mutually exclusive in promoter genome sequences, our results suggest that they may co-exist transiently as intermediates in telomeric sequences.