G-quadruplex DNA structure at G4–duplex junction (G4-duplex junction)

G-quadruplex (G4) DNA structures at G4–duplex junctions are specialized nucleic acid motifs formed in guanine-rich sequences where a four-stranded quadruplex transitions into a standard double-stranded helix (Nature Communications, 2021). These junctions are prevalent in regulatory regions of the genome, particularly within the promoters of oncogenes like c-MYC and at telomeric ends, where they serve as critical checkpoints for transcription and chromosomal stability (Nucleic Acids Research, 2020). In oncology, these structures are targeted because their stabilization can selectively downregulate the expression of genes driving tumor growth or trigger catastrophic DNA damage in cancer cells (Trends in Cancer, 2017). Small molecules such as Pidnarulex are designed to bind and stabilize these junctions, effectively halting the progression of the replication or transcription machinery (Journal of Clinical Oncology, 2019). The unique geometry of the junction provides a more specific binding pocket compared to the G-tetrad alone, potentially allowing for improved drug selectivity (Nature Chemistry, 2017). Beyond cancer, G4 structures are implicated in viral genome regulation and the pathogenesis of neurodegenerative diseases associated with nucleotide repeat expansions (Frontiers in Genetics, 2020). Despite their therapeutic potential, the widespread occurrence of G-rich sequences throughout the human genome poses significant challenges for achieving the high selectivity required to avoid disrupting normal cellular functions (Nature Reviews Drug Discovery, 2011).

Other names

G4-DNA junctionG-quadruplex-duplex interfaceG4-duplex hybrid structureG-quadruplex DNA

Stabilization of G-quadruplex structures at junctions to inhibit oncogene transcription, block telomerase elongation, induce DNA replication stress, and trigger DNA damage responses in malignant cells.