Computationally-designed aptamers targeting RAD51-BRCA2 interaction impair homologous recombination and induce...

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• The RAD51-BRCA2 interaction is crucial for homologous recombination (HR) DNA repair, vital for cancer cell survival.
• Targeting this interaction can sensitize cancer cells to chemotherapy.

Purpose of the Study:

• To design aptamers that selectively inhibit the RAD51-BRCA2 interaction.
• To evaluate the efficacy of these aptamers in modulating DNA repair and enhancing cancer treatment.

Main Methods:

• In silico aptamer design targeting RAD51.
• In vitro validation using biolayer interferometry (BLI) and fluorescence lifetime imaging microscopy (FLIM).
• Assessment in pancreatic cancer cells and 3D spheroid models.

Main Results:

• A high-affinity aptamer was identified that competes with BRCA2 for RAD51 binding.
• The aptamer impairs HR by disrupting RAD51/BRCA2 nuclear localization, increasing DNA damage.
• Combination with olaparib induces dose-dependent synthetic lethality in cancer cells.

Conclusions:

• Aptamer-based disruption of protein interactions in DNA repair pathways is a viable therapeutic strategy.
• This approach offers a promising new avenue for synthetic lethality-based cancer treatments.