The Major G-Quadruplex Formed in the Human Platelet-Derived Growth Factor Receptor β Promoter Adopts a Novel Broken-Strand Structure in K+ Solution

Overexpression of platelet-derived growth factor receptor beta (PDGFR-beta) has been associated with cancers and vascular and fibrotic disorders. PDGFR-beta has become an attractive target for the treatment of cancers and fibrotic disorders. DNA G-quadruplexes formed in the GC-rich nuclease hypersensitivity element of the human PDGFR-beta gene promoter have been found to inhibit PDGFR-beta transcriptional activity. Here we determined the major G-quadruplex formed in the PDGFR-beta promoter. Instead of using four continuous runs with three or more guanines, this G-quadruplex adopts a novel folding with a broken G-strand to form a primarily parallel-stranded intramolecular structure with three 1 nucleotide (nt) double-chain-reversal loops and one additional lateral loop. The novel folding of the PDGFR-beta promoter G-quadruplex emphasizes the robustness of parallel-stranded structural motifs with a 1 nt loop. Considering recent progress on G-quadruplexes formed in gene-promoter sequences, we suggest the 1 nt looped G(i)NG(j) motif may have been evolutionarily selected to serve as a stable foundation upon which the promoter G-quadruplexes can build. The novel folding of the PDGFR-beta promoter G-quadruplex may be attractive for small-molecule drugs that specifically target this secondary structure and modulate PDGFR-beta gene expression.