Dynamics and stability of polymorphic human telomeric G-quadruplex under tension

Area of Science:

• Biophysics
• Molecular Biology
• Genetics

Background:

• Human telomeres, capped by G-rich sequences, form G-quadruplex (G4) structures.
• Telomeric G4 stability and polymorphism are crucial for chromosome end maintenance.
• Understanding G4 dynamics is key to telomere biology and disease research.

Purpose of the Study:

• To characterize the equilibrium transitions and folding pathways of single-molecule human telomeric G4.
• To determine the mechanical stability and lifetime of different telomeric G4 states.
• To investigate the force-dependent free energy landscape of G4 folding.

Main Methods:

• Single-molecule force spectroscopy.
• Characterization of equilibrium transitions.
• Analysis of force-dependent transition rates.

Main Results:

• Identified three distinct folded states of telomeric G4 with varying lifetimes and mechanical stability.
• Revealed a kinetically favored folding pathway involving a short-lived intermediate.
• Determined the force-dependent transition free energy landscape for the G4 folding pathway.
• Discovered an ultra-long-lived telomeric G4 form with enhanced mechanical stability.

Conclusions:

• Telomeric G4 structures exhibit complex folding dynamics and multiple stable states.
• The mechanical stability and lifetime of G4 structures are force-dependent.
• An ultra-long-lived G4 state offers new insights into telomere structure and function.