Evidence for the Presence of a Guanine Quadruplex Forming Region within a Polypurine Tract of the Hypoxia Inducible Factor 1α Promoter

Abstract

The promoter of the hypoxia inducible factor 1 alpha (HIF-1alpha) gene has a polypurine/polypyrimidine tract (-65 to -85) overlapping or adjacent to several putative transcription factor binding sites, and we found that mutagenesis of this region diminished basal HIF-1alpha expression. Oligonucleotides representing this region of the HIF-1alpha promoter were analyzed by electrophoretic mobility shift, chemical probing, circular dichroism, and DNA polymerase arrest assays. The guanine-rich strand was found to form a parallel, unimolecular quadruplex in the presence of potassium that was further stabilized by two known quadruplex binding compounds, the cationic porphyrin TmPyP4 and the natural product telomestatin, while TmPyP2, a positional isomer of TmPyP4, did not stabilize quadruplex formation. These data suggest that a quadruplex structure may form in a region of the HIF-1alpha promoter that regulates basal HIF-1alpha expression.

An RNA-binding Protein, Lin28, Recognizes and Remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs It Regulates

“…G-quadruplexes are found within DNAs in eukaryotic telomeres (66); the promoter regions of some cancer-related genes, including BCL2 (67), KIT (68), MYB (69), MYC (70), HIF1A (71), hTERT (72), KRAS (73), RB (74), and VEGF (75); immunoglobulin gene switch regions (76); and ribosomal genes (77). G4-intercalating agents have been assessed for anticancer ther-apy (57,50,51).…”

Polymorphism of human telomeric quadruplex structures

“…This structural asymmetry determines the possibility of the formation of the two very closely related but distinct hybrid-1 and hybrid-2 structures. Unlike the G-rich sequences in gene promoter regions [57,58,[60][61][62][63][64][65][66][67], the telomeric DNA sequence is unique in that it contains the same tandem repeats with the same linker segments. Thus, in a telomeric sequence, any four-G-tract region has the same potential of forming an intramolecular G-quadruplex structure.…”

Synthesis, G‐Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2‐b]quinolines with One, Two, or Three Basic Side Chains

“…Compound 4 d is as good a stabiliser of the G4 sequence KRas21R (DT m = 13 8C) as of F21T. The G4 stabilising effect of compound 4 d was further evaluated with c-Kit1, [7a] HIF-1a, [25] and Hsp90C (comprising the full G4 sequence in the Hsp90 promoter region) [5] (Figure 2). The results showed a similar stabilisation of the oncogenic c-Kit1 G4 (DT m = 7 8C at 2 mm ligand concentration), compared with cKit2 and lower stabilisation of HIF-1a (DT m = 3 8C) relative to the remaining G4 structures.…”