Telomeric G-quadruplex DNA (Telomeric G4 DNA)

Telomeric G-quadruplex DNA refers to the four-stranded secondary structures formed by guanine-rich sequences at the ends of eukaryotic chromosomes (Rhodes, D. & Lipps, H. J., 2015, Nucleic Acids Research). These structures are composed of G-tetrads stabilized by Hoogsteen hydrogen bonding and monovalent cations like potassium (Neidle, S., 2017, Nature Reviews Chemistry). In humans, the telomeric repeat sequence (TTAGGG) can fold into these G-quadruplexes, which naturally inhibit the enzyme telomerase from extending the telomere (Biffi, G. et al., 2013, Nature Chemistry). Since telomerase is overexpressed in approximately 85-90% of cancer cells to maintain immortality, stabilizing these G-quadruplexes with small molecules is a potent strategy to induce senescence or apoptosis in malignant cells (Shay, J. W., 2016, Seminars in Cancer Biology). Beyond telomerase inhibition, G4 stabilization can disrupt the shelterin protein complex, leading to telomere dysfunction and a robust DNA damage response (Sfeir, A. & de Lange, T., 2012, Science). Small molecule ligands like CX-5461 are currently being investigated in clinical trials for their ability to target these structures in various cancers (Senhwa Biosciences, 2024). The therapeutic potential of targeting telomeric G4 DNA lies in its ability to selectively impact rapidly dividing cells with high telomerase activity.

Other names

Human telomeric G-quadruplexhTel G4Telomeric G4G-quadruplex DNA (telomeric)Telomeric G-quadruplex

Stabilization of G-quadruplex structures to inhibit telomerase activity and displace shelterin proteins, leading to telomere dysfunction and DNA damage response (Neidle, S., 2017, Nature Reviews Chemistry).