Human telomeric DNA forms parallel-stranded intramolecular G-quadruplex in K+ solution under molecular crowding...

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• The G-rich strand of human telomeric DNA can form G-quadruplex structures.
• G-quadruplexes inhibit telomerase activity, which is active in 85-90% of tumor cells, making them a cancer therapeutic target.
• Controversy exists regarding the precise G-quadruplex structure in physiological conditions.

Purpose of the Study:

• To investigate the structure of human telomeric DNA G-quadruplex under physiological conditions.
• To clarify the structural conformation favored in a molecularly crowded environment.
• To assess the stability and impact on telomerase of the formed G-quadruplex.

Main Methods:

• Utilized molecular crowding conditions with polyethylene glycol (PEG) at 40% (w/v).
• Analyzed the structural conformation of human telomeric DNA G-quadruplex.
• Assessed the stability of the G-quadruplex and its effect on telomerase processivity.

Main Results:

• Human telomeric DNA adopts a parallel-stranded G-quadruplex conformation under molecular crowding (40% PEG).
• This parallel-stranded G-quadruplex exhibits unusual stability.
• The G-quadruplex formation significantly impacts telomerase processivity.

Conclusions:

• The parallel-stranded G-quadruplex is likely the favored structure in the crowded physiological environment of cells.
• Findings suggest that drug design targeting human telomeric G-quadruplexes should consider this parallel-stranded conformation.
• This research provides critical insights for structure-based cancer drug development.