Indoloquinoxaline ligand targets TERRA RNA G-quadruplex to disrupt ALT cancer telomere upkeep
- An indoloquinoxaline scaffold was developed to bind the RNA G-quadruplex of TERRA, a long non-coding RNA important in telomerase-independent (ALT) cancers.
- Biophysics showed tight, selective recognition; NMR and modeling point to stacking on the terminal G-tetrad.
- The ligand weakens TERRA-TRF2 association and shifts TERRA levels and ALT-related gene expression.
- In ALT-positive U2OS cells it reaches the nucleus, causing telomere-linked DNA damage, S-phase arrest and apoptosis.
💡 Points Based on the abstract
Flat polyaromatics stacking on a terminal G-tetrad is the classic G4 recipe, so selectivity over DNA quadruplexes and the many other RNA G4s is the open question. U2OS DNA damage could also come from binding telomeric DNA G4. A TERRA-mutant or G-to-U control and a TRF2-knockdown rescue would tie the phenotype to TERRA.
Small Molecule Modulation of TERRA RNA Quadruplex Reprograms ALT‐Telomere Maintenance ↗