Nucleic Acids Research Advance Access originally published online on November 5, 2007
Nucleic Acids Research 2007 35(22):7698-7713; doi:10.1093/nar/gkm538
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Nucleic Acids Research, 2007, Vol. 35, No. 22 7698-7713
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Characterization of the G-quadruplexes in the duplex nuclease hypersensitive element of the PDGF-A promoter and modulation of PDGF-A promoter activity by TMPyP4
1College of Pharmacy, 1703 E. Mabel, University of Arizona, Tucson, Arizona 85721, 2Arizona Cancer Center, 1515 N. Campbell Avenue, Tucson, Arizona 85724, 3Department of Chemistry, University of Arizona, Tucson, Arizona, 85721 and 4BIO5 Collaborative Research Institute, 1657 E. Helen Street, Tucson, Arizona 85721, USA
*To whom correspondence should be addressed. Tel: +1 520 626 5622; Fax: +1 520 626 5623; Email: hurley{at}pharmacy.arizona.edu
Received April 13, 2007. Revised June 27, 2007. Accepted June 28, 2007.
The proximal 5'-flanking region of the human platelet-derived growth factor A (PDGF-A) promoter contains one nuclease hypersensitive element (NHE) that is critical for PDGF-A gene transcription. On the basis of circular dichroism (CD) and electrophoretic mobility shift assay (EMSA), we have shown that the guanine-rich (G-rich) strand of the DNA in this region can form stable intramolecular parallel G-quadruplexes under physiological conditions. A Taq polymerase stop assay has shown that the G-rich strand of the NHE can form two major G-quadruplex structures, which are in dynamic equilibrium and differentially stabilized by three G-quadruplex-interactive drugs. One major parallel G-quadruplex structure of the G-rich strand DNA of NHE was identified by CD and dimethyl sulfate (DMS) footprinting. Surprisingly, CD spectroscopy shows a stable parallel G-quadruplex structure formed within the duplex DNA of the NHE at temperatures up to 100°C. This structure has been characterized by DMS footprinting in the double-stranded DNA of the NHE. In transfection experiments, 10 µM TMPyP4 reduced the activity of the basal promoter of PDGF-A 
40%, relative to the control. On the basis of these results, we have established that ligand-mediated stabilization of G-quadruplex structures within the PDGF-A NHE can silence PDGF-A expression.
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