G-quadruplexes mark alternative lengthening of telomeres

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Alternative Lengthening of Telomere (ALT) is a telomere maintenance mechanism used by 10-15% of human cancers.
• The precise role and prevalence of non-canonical nucleic acid structures in ALT cancers are not fully understood.

Purpose of the Study:

• To investigate the prevalence and role of R-loops and G-quadruplexes (G4) in ALT cancers.
• To explore the relationship between these structures and telomere maintenance in ALT.
• To assess the potential of G4 as a biomarker for ALT+ tumors.

Main Methods:

• Comparative analysis of R-loop and G4 levels in ALT-positive (ALT+) versus telomerase-positive (TERT+) cells.
• Investigation of the interdependent relationship and spatial linkage between G4 and R-loops (G-loops) at telomeres.
• Assessment of the impact of G4 and R-loop stabilization on ALT activity and cytotoxicity.
• Analysis of nuclear G4 signals in low-grade glioma tumors from ALT+ and TERT+ patients.

Main Results:

• ALT+ cells exhibit significantly higher levels of R-loops and G4 compared to TERT+ cells.
• G4 structures are localized at telomeres, correlating with telomere length and DNA damage markers.
• A novel structure, G-loops, formed by the spatial linkage of G4 and R-loops, was identified at telomeres.
• Co-stabilization of G4 and R-loops enhances ALT activity but leads to synergistic cytotoxicity at higher doses.
• Distinct nuclear G4 signal patterns differentiate ALT+ from TERT+ low-grade glioma tumors.

Conclusions:

• G-quadruplexes (G4) represent a novel hallmark of ALT cancers.
• The interdependent relationship between G4 and R-loops (G-loops) is crucial for ALT.
• G4 structures hold potential as biomarkers for identifying ALT+ tumors and as therapeutic targets.