Human telomerase reverse transcriptase promoter G-quadruplex (hTERT promoter G4)

The Human telomerase reverse transcriptase (hTERT) promoter G-quadruplex is a non-canonical DNA secondary structure located within the GC-rich core promoter region of the hTERT gene (PMID: 27103548). This structure is formed by guanine-rich sequences that stack into G-tetrads, stabilized by Hoogsteen hydrogen bonding and monovalent cations. Biologically, these G-quadruplexes act as transcriptional silencers; when stabilized, they prevent the binding of essential transcription factors and the assembly of the transcription machinery, thereby downregulating TERT expression (PMID: 30103543). In approximately 90% of human cancers, TERT is overexpressed to maintain telomere length, providing the cellular immortality necessary for tumor progression. Mutations in the hTERT promoter, such as C228T and C250T, are frequently observed in various malignancies and can influence G-quadruplex stability or create new binding sites for transcription factors like GABP (PMID: 32663434). Small-molecule ligands designed to target and stabilize the hTERT promoter G-quadruplex are being developed as potential anti-cancer therapies to silence telomerase activity and induce senescence in cancer cells. However, achieving high selectivity for the hTERT G-quadruplex over the thousands of other G4 structures in the human genome remains a significant therapeutic challenge (PMID: 32824111).

Other names

hTERT G-quadruplexTERT promoter G-quadruplexhTERT G4 DNATERT G4

Stabilization of the G-quadruplex structure within the hTERT promoter region to sterically hinder the binding of transcription factors (such as Sp1 and c-Myc) and RNA polymerase II, thereby suppressing TERT gene transcription and inhibiting telomerase activity (PMID: 31100571, 32824111).