The dynamic character of the BCL2 promoter i-motif provides a mechanism for modulation of gene expression by compounds that bind selectively to the alternative DNA hairpin structure.
The dynamic character of the BCL2 promoter i-motif provides a mechanism for modulation of gene expression by compounds that bind selectively to the alternative DNA hairpin structure.
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DOI：
10.1021/ja410934b
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发表时间：
2014-03-19
影响因子：
15
通讯作者：
Hurley LH
中科院分区：
文献类型：
--
作者：
Kendrick S;Kang HJ;Alam MP;Madathil MM;Agrawal P;Gokhale V;Yang D;Hecht SM;Hurley LH
It is generally accepted that DNA predominantly exists in duplex form in cells. However, under torsional stress imposed by active transcription, DNA can assume nonduplex structures. The BCL2 promoter region forms two different secondary DNA structures on opposite strands called the G-quadruplex and the i-motif. The i-motif is a highly dynamic structure that exists in equilibrium with a flexible hairpin species. Here we identify a pregnanol derivative and a class of piperidine derivatives that differentially modulate gene expression by stabilizing either the i-motif or the flexible hairpin species. Stabilization of the i-motif structure results in significant upregulation of the BCL2 gene and associated protein expression; in contrast, stabilization of the flexible hairpin species lowers BCL2 levels. The BCL2 levels reduced by the hairpin-binding compound led to chemosensitization to etoposide in both in vitro and in vivo models. Furthermore, we show antagonism between the two classes of compounds in solution and in cells. For the first time, our results demonstrate the principle of small molecule targeting of i-motif structures in vitro and in vivo to modulate gene expression.
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影响因子：
15
作者：
Bejugam, Mallesham;Sewitz, Sven;Shirude, Pravin S.;Rodriguez, Raphael;Shahid, Ramla;Balasubramanian, Shankar
通讯作者：
Balasubramanian, Shankar
DOI：
10.1038/nrg3296
发表时间：
2012-11
期刊：
Nature reviews. Genetics
影响因子：
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作者：
通讯作者：
--
影响因子：
14.9
作者：
Guo K;Gokhale V;Hurley LH;Sun D
通讯作者：
Sun D
影响因子：
14.9
作者：
Cui Y;Koirala D;Kang H;Dhakal S;Yangyuoru P;Hurley LH;Mao H
通讯作者：
Mao H
影响因子：
4.8
作者：
Gonzalez, Veronica;Guo, Kexiao;Sun, Daekyu
通讯作者：
Sun, Daekyu