Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription

被引:1900
作者
Siddiqui-Jain, A
Grand, CL
Bearss, DJ
Hurley, LH [1 ]
机构
[1] Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA
[2] Univ Arizona, Dept Chem, Tucson, AZ 85721 USA
[3] Arizona Canc Ctr, Tucson, AZ 85724 USA
关键词
D O I
10.1073/pnas.182256799
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The nuclease hypersensitivity element III1 upstream of the P1 promoter of c-MYC controls 85-90% of the transcriptional activation of this gene. We have demonstrated that the purine-rich strand of the DNA in this region can form two different intramolecular G-quadruplex structures, only one of which seems to be biologically relevant. This biologically relevant structure is the kinetically favored chair-form G-quadruplex, which is destabilized when mutated with a single G --> A transition, resulting in a 3-fold increase in basal transcriptional activity of the c-MYC promoter. The cationic porphyrin TMPyP4, which has been shown to stabilize this G-quadruplex structure, is able to suppress further c-MYC transcriptional activation. These results provide compelling evidence that a specific G-quadruplex structure formed in the c-MYC promoter region functions as a transcriptional repressor element. Furthermore, we establish the principle that c-MYC transcription can be controlled by ligand-mediated G-quadruplex stabilization.
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收藏
页码:11593 / 11598
页数:6
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