Solution structures of all parallel-stranded monomeric and dimeric G-quadruplex scaffolds of the human c-kit2 promoter.
Solution structures of all parallel-stranded monomeric and dimeric G-quadruplex scaffolds of the human c-kit2 promoter.
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DOI：
10.1093/nar/gkq558
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发表时间：
2010-10
影响因子：
14.9
通讯作者：
Patel DJ
中科院分区：
文献类型：
--
作者：
Kuryavyi V;Phan AT;Patel DJ
先前的研究表明，位于转录起始位点上游的几种原癌基因DNA启动子的核酸酶超敏区含有富含鸟嘌呤的片段，这些片段在单价阳离子溶液中形成由堆叠的G·G·G·G四联体稳定的分子内G-四联体。人类c-kit致癌启动子是治疗胃肠道肿瘤的重要靶点，它包含两段富含鸟嘌呤的片段，分别命名为c-kit 1和c-kit 2。我们以前的核磁共振（NMR）为基础的研究报道了新的G-四链体支架的c-kit 1启动子在含K+的溶液中，在那里我们首次表明，即使是一个孤立的鸟嘌呤参与G-四分体的形成。这些基于NMR的研究现在扩展到c-kit 2启动子，它采用两种不同的全平行链构象在缓慢的交换，其中之一形成一个单体G-四链体（形式-I）在20 mM K+-含有溶液和其他一个新的二聚体G-四链体（形式-II）在100 mM K+-含有溶液。c-kit 2启动子二聚体II型G-四链体采用了前所未有的全平行链拓扑结构，其中单个c-kit 2启动子链跨越一对包含三个G-四链体层的全平行链G-四链体，其以3′至5′端方向排列，G-四链体之间的堆叠连续性由夹心A·A非典型对介导。我们建议，链交换富含鸟嘌呤的片段内的重组事件，可能是介导的突触中间体，涉及基因间的平行链二聚体G-四链体。
Previous studies have demonstrated that nuclease hypersensitivity regions of several proto-oncogenic DNA promoters, situated upstream of transcription start sites, contain guanine-rich tracts that form intramolecular G-quadruplexes stabilized by stacked G•G•G•G tetrads in monovalent cation solution. The human c-kit oncogenic promoter, an important target in the treatment of gastrointestinal tumors, contains two such stretches of guanine-rich tracts, designated c-kit1 and c-kit2. Our previous nuclear magnetic resonance (NMR)-based studies reported on the novel G-quadruplex scaffold of the c-kit1 promoter in K+-containing solution, where we showed for the first time that even an isolated guanine was involved in G-tetrad formation. These NMR-based studies are now extended to the c-kit2 promoter, which adopts two distinct all-parallel-stranded conformations in slow exchange, one of which forms a monomeric G-quadruplex (form-I) in 20 mM K+-containing solution and the other a novel dimeric G-quadruplex (form-II) in 100 mM K+-containing solution. The c-kit2 promoter dimeric form-II G-quadruplex adopts an unprecedented all-parallel-stranded topology where individual c-kit2 promoter strands span a pair of three-G-tetrad-layer-containing all-parallel-stranded G-quadruplexes aligned in a 3′ to 5′-end orientation, with stacking continuity between G-quadruplexes mediated by a sandwiched A•A non-canonical pair. We propose that strand exchange during recombination events within guanine-rich segments, could potentially be mediated by a synapsis intermediate involving an intergenic parallel-stranded dimeric G-quadruplex.
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影响因子：
15
作者：
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通讯作者：
Balasubramanian, Shankar
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影响因子：
14.9
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通讯作者：
Yang D
影响因子：
14.9
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Vorlícková M
影响因子：
4.6
作者：
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