Solution structure of the biologically relevant g-quadruplex element in the human c-MYC promoter. implications for g-quadruplex stabilization
Solution structure of the biologically relevant g-quadruplex element in the human c-MYC promoter. implications for g-quadruplex stabilization
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DOI：
10.1021/bi048242p
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发表时间：
2005-02-15
期刊：
影响因子：
2.9
通讯作者：
Yang, DZ
中科院分区：
文献类型：
--
作者：
Ambrus, A;Chen, D;Yang, DZ
c-MYC 启动子的核酸酶超敏元件 III1 (NHE III1) 强烈控制 c-MYC 癌基因的转录活性。 NHE 111 元件的富含嘌呤链已被证明是 G-四链体结构形成后 c-MYC 转录的沉默元件。我们通过 NMR 确定了钾溶液中该消音器元件的主要 G-四联体结构。 G-四链体结构采用分子内平行链四链体构象，具有三个鸟嘌呤四分体和三个侧环，包括两个单核苷酸侧环和一个双核苷酸侧环，连接四个鸟嘌呤链。三个侧环非常稳定且轮廓分明。 3'-侧翼序列形成稳定的折返堆叠构象，覆盖 G-四链体结构的顶端。 5'侧翼的 A 和 G 碱基覆盖了 G 四联体的底端，腺嘌呤与底部四联体堆叠得很好。本文报道了在癌基因 (c-MYC) 启动子区域中发现的第一个 G-四链体的溶液结构。这种 G-四链体结构极其稳定，具有与 c-MYC 启动子的野生型 27 聚体富含嘌呤的 NHE III1 序列相似的解链温度 (>85°C)。这种主要的四链体结构已被证明具有生物学相关性，本研究揭示的结构信息为设计专门针对 c-MYC G 四链体结构并调节基因表达的新候选药物提供了重要基础。
The nuclease hypersensitivity element III1, (NHE III1) of the c-MYC promoter strongly controls the transcriptional activity of the c-MYC oncogene. The purine-rich strand of the NHE 111, element has been shown to be a silencer element for c-MYC transcription upon formation of a G-quadruplex structure. We have determined the predominant G-quadruplex structure of this silencer element in potassium solution by NMR. The G-quadruplex structure adopts an intramolecular parallel-stranded quadruplex conformation with three guanine tetrads and three side loops, including two single-nucleotide side loops and one double-nucleotide side loop, that connect the four guanine strands. The three side loops are very stable and well-defined. The 3'-flanking sequence forms a stable fold-back stacking conformation capping the top end of the G-quadruplex structure. The 5'-flanking A and G bases cap the bottom end of the G-quadruplex, with the adenine stacking very well with the bottom tetrad. This paper reports the first solution structure of a G-quadruplex found to form in the promoter region of an oncogene (c-MYC). This G-quadruplex structure is extremely stable, with a similar melting temperature (>85degreesC) to that of the wild-type 27-mer purine-rich NHE III1 sequence of the c-MYC promoter. This predominant quadruplex structure has been shown to be biologically relevant, and the structural information revealed in this research provides an important basis for the design of new drug candidates that specifically target the c-MYC G-quadruplex structure and modulate gene expression.