Structural Insights into an Antiparallel Chair-Type G-Quadruplex From the Intron of NOP56 Oncogene

Area of Science:

• Structural biology
• Molecular biology
• Genetics

Background:

• G-quadruplex (G4) structures are crucial in biological processes like gene regulation.
• Nucleolar protein 56 (NOP56) is vital for ribosome biogenesis and is overexpressed in cancers, making it a therapeutic target.

Purpose of the Study:

• To determine the high-resolution structure of a novel G4 formed by a DNA sequence from NOP56 intron 1.
• To investigate the interaction of the G4 ligand pyridostatin (PDS) with this structure.
• To assess the therapeutic potential of targeting this intronic G4 structure.

Main Methods:

• Solution nuclear magnetic resonance (NMR) spectroscopy for high-resolution structure determination.
• Melting temperature assays to evaluate ligand binding and stabilization.
• Cancer cell line experiments to assess the effect of PDS on NOP56 mRNA levels.

Main Results:

• The first reported antiparallel chair-type G4 structure from NOP56 intron 1 was elucidated.
• The NOP56-G4 structure features two G-tetrads, a C·G·C·G tetrad, and a C∙C base pair.
• Pyridostatin (PDS) binds to the terminal G-tetrad, increasing the G4 melting temperature by ~14 °C and reducing NOP56 mRNA in cancer cells.

Conclusions:

• This study provides an unprecedented structural basis for a unique intronic G4 structure in NOP56.
• Targeting intronic G4 structures offers a feasible strategy for gene regulation.
• The findings open new avenues for G4 structure-based drug design and cancer therapeutics.