An intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands formed in the human BCL-2 promoter region in solution
An intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands formed in the human BCL-2 promoter region in solution
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DOI：
10.1021/ja055636a
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发表时间：
2006-02-01
影响因子：
15
通讯作者：
Yang, DZ
中科院分区：
文献类型：
--
作者：
Dai, JX;Dexheimer, TS;Yang, DZ
我们报告的第一个G-四链体结构中形成的启动子区的人bcl-2。Bcl-2是一种有效的癌蛋白，其作为细胞凋亡的抑制剂起作用，并且已经发现在广泛的人类肿瘤中异常过表达。P1启动子上游的一个富含GC的区域在调节bcl-2癌基因的转录活性中起着重要作用。该区域的富含嘌呤的链含有多个鸟嘌呤，并且在含K+的溶液中可以形成三种不同的分子内G-四链体。其中，在中间四个连续鸟嘌呤运行中形成的G-四链体已被证明是最稳定的G-四链体结构，同时它也是环异构体的混合物。主要的G-四链体结构形成在这个区域进行了研究，通过NMR。我们的研究结果表明，一个独特的分子内G-四链体结构的混合平行/反平行G-链的一种新的折叠。这种G-四链体结构包含三个G-四链体，由一个单核苷酸双链反转侧环和两个侧环连接。bcl-2启动子序列中的第一个三核苷酸CGC环形成侧环，而不是在c-MYC启动子中的类似序列中观察到的双链反转侧环，这似乎在很大程度上决定了bcl-2 G-四链体的整体折叠。此外，bcl-2和c-MYC启动子序列均含有G3 NG 3序列基序，其形成稳定的双链反转平行链结构基序。这种主要的bcl-2 G-四链体代表了一个有吸引力的新靶点，用于设计特异性调节bcl-2基因表达的新抗癌药物。
We report the first G-quadruplex structure formed in the promoter region of the human bcl-2. Bcl-2 is a potent oncoprotein that functions as an inhibitor of cell apoptosis and has been found to be aberrantly overexpressed in a wide range of human tumors. A highly GC-rich region upstream of the P1 promoter plays an important role in the regulation of the transcriptional activity of the bcl-2 oncogene. The purine-rich strand of this region contains multiple runs of guanines and can form three distinct intramolecular G-quadruplexes in K+-containing solution. Of these, the G-quadruplex formed within the middle four consecutive guanine runs has been shown to be the most stable G-quadruplex structure, while it is also a mixture of loop isomers. The predominant G-quadruplex structure formed in this region was studied by NMR. Our results demonstrate a novel folding of a unique intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands. This G-quadruplex structure contains three G-tetrads connected with a single-nucleotide double-chain-reversal side loop and two lateral loops. The first three-nucleotide CGC loop in the bcl-2 promoter sequence forms a lateral loop, as opposed to a double-chain-reversal side loop observed in a similar sequence in the c-MYC promoter, which appears to largely determine the overall folding of the bcl-2 G-quadruplex. Furthermore, both the bcl-2 and c-MYC promoter sequences contain the G3NG3sequence motif, which forms a stable double-chain-reversal, parallel-stranded structural motif. This predominant bcl-2 G-quadruplex represents an attractive novel target for the design of new anticancer drugs that specifically modulate bcl-2 gene expression.