Targeting proto-oncogene B-MYB G-quadruplex with a nucleic acid-based fluorescent probe

Area of Science:

• Molecular Biology
• Biochemistry
• Genetics

Background:

• The B-MYB gene is vital for cell growth and survival, with abnormal expression linked to lung cancer.
• Oncogenes, including B-MYB, can form G-quadruplex (G4) structures in their promoter regions, influencing gene regulation.
• These G4 structures represent potential targets for cancer drug development.

Purpose of the Study:

• To design and characterize a probe for specifically identifying a G-quadruplex in the B-MYB gene promoter.
• To investigate the interaction of acridine derivative ligands with the B-MYB G4 structure.
• To assess the potential of this probe and ligands for therapeutic applications in lung cancer.

Main Methods:

• Design of a probe combining an acridine derivative ligand with a DNA segment complementary to the target G4 sequence.
• Biophysical characterization including stability, affinity, and fluorescence studies of the probe-G4 interaction.
• Cellular studies to confirm G4 formation, probe co-localization, and the effect of ligands on G4s in vivo.

Main Results:

• Acridine derivative ligands (C5NH2, C8NH2) effectively stabilized the B-MYB G4 structure with moderate affinity.
• Ligands altered G4 topology and showed enhanced fluorescence upon binding, indicating successful G4 interaction.
• The target sequence formed a G4 structure, even with a nucleotide tail, and cellular studies confirmed probe co-localization.

Conclusions:

• A specific probe and acridine ligands were developed to target the B-MYB gene promoter G4.
• These findings demonstrate the potential of targeting B-MYB G4s for lung cancer therapy.
• The study validates the formation and detection of G4 structures in the B-MYB oncogene promoter.