A New G-Quadruplex with Hairpin Loop Immediately Upstream of the Human BCL2 P1 Promoter Modulates Transcription.
A New G-Quadruplex with Hairpin Loop Immediately Upstream of the Human BCL2 P1 Promoter Modulates Transcription.
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DOI：
10.1021/jacs.5b08596
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发表时间：
2016-03-02
影响因子：
15
通讯作者：
Yang D
中科院分区：
文献类型：
--
作者：
Onel B;Carver M;Wu G;Timonina D;Kalarn S;Larriva M;Yang D
BCL2基因的异常过表达与许多人类肿瘤有关。我们在人类BCL2基因P1启动子的上游发现了一个新的28聚体g -四重体形成序列P1G4。通过启动子驱动的荧光素酶测定，P1G4被证明是一种转录抑制因子；g -四聚体相互作用的化合物TMPyP4可显著增强其抑制作用。DMS足迹显示，生理盐条件下，P1G4序列容易形成g -四重体。P1G4和先前鉴定的Pu39 g -四联体似乎在BCL2 P1启动子的邻近区域独立形成。在包含Pu39和P1G4的扩展BCL2 P1启动子区域中，P1G4似乎在抑制转录活性方面发挥更主要的作用。通过核磁共振光谱分析，P1G4 g -四联体似乎是两种平行结构的新型动态平衡，一种是有两个1-nt环和一个12-nt中间环的规则结构，另一种是有三个1-nt环和一个11-nt中间环的断裂链；这两种结构在长环路中都采用了新颖的发夹（茎环双相）构象。两个密切相关的结构的动态平衡和独特的发夹环构象是P1G4序列所特有的，是P1G4四联体与其他平行结构的区别。P1G4和Pu39在BCL2 P1启动子邻近区域的存在，提示BCL2基因转录的精确调控机制。独特的P1G4 g -四重体可能为小分子调节BCL2基因转录提供了一个特定的靶点。
The abnormal over-expression of the BCL2 gene is associated with many human tumors. We found a new 28-mer G-quadruplex-forming sequence, P1G4, immediately upstream of the human BCL2 gene P1 promoter. The P1G4 is shown to be a transcription repressor using a promoter-driven luciferase assay; its inhibitory effect can be markedly enhanced by the G-quadruplex-interactive compound TMPyP4. G-quadruplex can readily form in the P1G4 sequence under physiological salt condition as shown by DMS footprinting. P1G4 and previously identified Pu39 G-quadruplexes appear to form independently in adjacent regions in the BCL2 P1 promoter. In the extended BCL2 P1 promoter region containing both Pu39 and P1G4, P1G4 appears to play a more dominant role in repressing the transcriptional activity. Using NMR spectroscopy, the P1G4 G-quadruplex appears to be a novel dynamic equilibrium of two parallel structures, one regular with two 1-nt loops and a 12-nt middle loop and another broken-strand with three 1-nt loops and a 11-nt middle loop; both structures adopt a novel hairpin (stem-loop duplex) conformation in the long loop. The dynamic equilibrium of two closely related structures and the unique hairpin loop conformation are specific to the P1G4 sequence and distinguish the P1G4 quadruplex from other parallel structures. The presence of P1G4 and Pu39 in adjacent regions of the BCL2 P1 promoter suggests a mechanism for precise regulation of BCL2 gene transcription. The unique P1G4 G-quadruplex may provide a specific target for small molecules to modulate BCL2 gene transcription.
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影响因子：
11.4
作者：
SETO, M;JAEGER, U;KORSMEYER, SJ
通讯作者：
KORSMEYER, SJ
影响因子：
158.5
作者：
PEZZELLA, F;TURLEY, H;MASON, DY
通讯作者：
MASON, DY
DOI：
10.1073/pnas.83.14.5214
发表时间：
1986-07-01
影响因子：
11.1
作者：
TSUJIMOTO, Y;CROCE, CM
通讯作者：
CROCE, CM
影响因子：
15
作者：
Agrawal P;Lin C;Mathad RI;Carver M;Yang D
通讯作者：
Yang D
影响因子：
15
作者：
Dexheimer, TS;Sun, D;Hurley, LH
通讯作者：
Hurley, LH