MYC promoter G-quadruplex (MYC G4) (MYC G4)

GC-rich DNA binding sites for MYC-controlled transcription, primarily the G-quadruplex (G4) structures within the MYC promoter, are critical regulatory elements that govern the expression of the MYC oncogene. MYC is a master transcription factor that regulates thousands of genes involved in cell growth, metabolism, and apoptosis, and its overexpression is a driver in a vast majority of human cancers (Siddiqui-Jain et al., 2002). The most prominent of these sites is the NHE III1 element in the MYC proximal promoter, which can transition between a double-stranded form and a four-stranded G-quadruplex structure that physically obstructs transcription (Brooks & Hurley, 2009). Small molecules such as APTO-253 and CX-5461 are designed to stabilize these G-quadruplexes, effectively silencing MYC expression and inducing cell cycle arrest or apoptosis in MYC-dependent cancer cells (Local et al., 2018). Additionally, MYC is recruited to other GC-rich promoters through interactions with proteins like SP1, making these regions focal points for transcriptional interference (Miller et al., 2012). While targeting DNA structures offers a way to inhibit the traditionally 'undruggable' MYC protein, therapeutic challenges include ensuring selectivity over other genomic G-quadruplexes and managing potential genotoxicity (Balasubramanian et al., 2011). These sites represent a novel class of therapeutic targets that move beyond traditional protein-centric drug discovery. Clinical development of G4-stabilizers continues to explore their potential in treating refractory leukemias and solid tumors.

Other names

GC-rich DNA binding sites for MYC-controlled transcriptionNHE III1 elementMYC response elementG4 DNAE-boxMYC promoter G-quadruplex

Stabilization of G-quadruplex DNA structures and displacement of transcription factors from GC-rich promoter regions