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Nucleic Acids Research Advance Access published online on July 9, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn380
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© 2008 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.

Structural Biology

Intramolecularly folded G-quadruplex and i-motif structures in the proximal promoter of the vascular endothelial growth factor gene

Kexiao Guo1, Vijay Gokhale2, Laurence H. Hurley2,3,4 and Daekyu Sun2,*

1Department of Biochemistry and Molecular Biophysics, University of Arizona, 2Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, 3Arizona Cancer Center, 1515 N. Campbell Ave., Tucson, AZ 85724 and 4BIO5 Collaborative Research Institute, 1657 E. Helen St., Tucson, AZ 85721, USA

*To whom correspondence should be addressed. Tel: +1 520 626 0323; Fax: +1 520 626 4824; Email: sun{at}pharmacy.arizona.edu Correspondence may also be addressed to Laurence Hurley. Tel: +1 520 626 5622; Fax: +1 520 626 4824; Email: hurley{at}pharmacy.arizona.edu

Received April 28, 2008. Revised May 28, 2008. Accepted May 29, 2008.

A polyguanine/polycytosine (polyG/polyC) tract in the proximal promoter of the vascular endothelial growth factor (VEGF) gene is essential for transcriptional activation. The guanine-rich (G-rich) and cytosine-rich (C-rich) strands on this tract are shown to form specific secondary structures, characterized as G-quadruplexes and i-motifs, respectively. Mutational analysis of the G-rich strand combined with dimethyl sulfate (DMS) footprinting, a polymerase stop assay, and circular dichroism (CD) spectroscopy revealed that the G-quadruplex containing a 1:4:1 double-chain reversal loop is the most thermodynamically stable conformation that this strand readily adopts. These studies provide strong evidence that the size of loop regions plays a critical role in determining the most favored folding pattern of a G-quadruplex. The secondary structure formed on the complementary C-rich strand was also determined by mutational analysis combined with Br2 footprinting and CD spectroscopy. Our results reveal that at a pH of 5.9 this strand is able to form an intramolecular i-motif structure that involves six C–C+ base pairs and a 2:3:2 loop configuration. Taken together, our results demonstrate that the G-quadruplex and i-motif structures are able to form on the G- and C-rich strands, respectively, of the polyG/polyC tract in the VEGF proximal promoter under conditions that favor the transition from B-DNA to non-B-DNA conformations.


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