c-MYC promoter G-quadruplex (MycG4)

The c-MYC promoter G-quadruplex is a four-stranded DNA secondary structure formed within the nuclease hypersensitivity element III1 (NHE III1) located upstream of the P1 promoter of the c-MYC oncogene, specifically involving four consecutive guanine runs (Myc2345) in a 27-nucleotide purine-rich segment. It adopts a biologically relevant parallel-stranded intramolecular conformation with three guanine tetrads and short loops, exhibiting high stability in potassium solutions. This structure functions as a transcriptional repressor by silencing c-MYC expression, a proto-oncogene critical for cell proliferation, apoptosis, and cancer progression; its disruption via mutations increases c-MYC transcription threefold. Recent evidence also indicates a positive regulatory role, where the folded G-quadruplex recruits transcription factors like SP1 and CNBP, alters chromatin landscape including histone modifications and nucleosome occupancy, and enhances P1 promoter activity in endogenous contexts. It serves as a binding hub for multiple transcription factors, particularly at highly expressed cancer gene promoters, competing with double-stranded DNA motifs. Small molecules such as TMPyP4 bind and stabilize this G-quadruplex, suppressing c-MYC expression and downstream targets like hTERT and ODC, positioning it as a therapeutic target for anticancer agents that modulate oncogene transcription through DNA structure stabilization rather than sequence-specific interactions.

Other names

c-MYC NHE III1 G-quadruplexPu27 G-quadruplexMyc2345 G-quadruplex

Stabilization of G-quadruplex structure to repress c-MYC transcription