A Hybrid G‑Quadruplex Structure Formed by a Sequence from the MAX Gene.

Area of Science:

• Structural Biology
• Genetics
• Biochemistry

Background:

• The MAX gene encodes a transcription factor that partners with the oncoprotein MYC.
• G-quadruplexes (G4s) are non-canonical DNA structures implicated in various biological processes.
• Understanding G4 structures is crucial for developing targeted therapies.

Purpose of the Study:

• To elucidate the NMR solution structure of a specific G-quadruplex (G4) DNA sequence from the MAX gene.
• To characterize the unique topology and stability of this MAX G4 structure.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy was used to determine the solution structure.
• Analysis of DNA sequence d-[AG3AG4A2G4TGA2G4A] from the MAX gene's first intron.

Main Results:

• A unimolecular G4 with a [3 + 1] hybrid topology was identified, featuring propeller, diagonal, and lateral loops.
• The G4 exhibits a stable structure under physiological conditions, even without annealing.
• Unusual features include a G·(A-G) triad in the diagonal loop and a T·G base pair in the lateral loop.
• The MAX G4 acts as a barrier to DNA polymerase.

Conclusions:

• This study reports the first example of this unique G4 topology with unmodified nucleotides.
• The findings offer insights into G4 folding and highlight the MAX G4 as a potential therapeutic target.
• The stability and polymerase barrier properties suggest a role in gene regulation.