Parallel-stranded G-quadruplex DNA (G4 DNA)

G-quadruplexes (G4s) are non-canonical secondary structures formed in guanine-rich DNA or RNA sequences through Hoogsteen hydrogen bonding, which creates square planar arrangements called G-tetrads. The all-parallel-stranded G-quadruplex is a specific topological variant where all four strands of the DNA backbone are oriented in the same direction, a configuration frequently observed in the promoter regions of potent oncogenes and within human telomeric repeats (Rhodes & Lipps, 2015). These structures, including tetramolecular forms (DNA4) and specific lengths like 18-mer sequences, act as molecular switches that regulate essential genomic functions, including DNA replication, telomere maintenance, and the transcription of genes such as c-MYC, KRAS, and BCL-2 (Balasubramanian et al., 2011). In oncology, G4 structures are considered high-value therapeutic targets because their stabilization by small-molecule ligands can lead to transcriptional repression of drivers of malignancy or induce telomere dysfunction and subsequent apoptosis in cancer cells (Hansel-Hertsch et al., 2017). Drugs like Pidnarulex (CX-5461) and Quarfloxin have been developed to exploit these mechanisms by stabilizing G4 structures and inducing a DNA damage response specifically in cancer cells (Xu et al., 2017). However, the ubiquity of G-rich sequences across the genome presents challenges for achieving high specificity and minimizing off-target toxicity (Spiegel et al., 2020).

Other names

G-quadruplexG4-DNAG-tetraplexParallel G4Tetramolecular G-quadruplexDNA4 G-quadruplexG-rich DNA structure

Stabilization of G-quadruplex structures to inhibit transcription of oncogenes, interfere with telomerase-mediated telomere elongation, or induce DNA damage responses and replication stress.