Targeting BRCA1- and BRCA2-deficient cells with RAD52 small molecule inhibitors

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• RAD52 is a key protein in the homologous recombination (HR) pathway, essential for maintaining genome integrity.
• While RAD52 mutations alone have no significant phenotype in mammals, they are lethal when combined with mutations in BRCA1, BRCA2, PALB2, and RAD51C, suggesting RAD52 as a potential cancer therapy target.
• RAD52 exhibits ssDNA annealing and DNA strand exchange activities in vitro.

Purpose of the Study:

• To identify small molecule inhibitors of RAD52's ssDNA annealing activity.
• To characterize these inhibitors using biochemical and cell-based assays.
• To explore the therapeutic potential of RAD52 inhibitors for cancer treatment.

Main Methods:

• Screened a library of 372,903 compounds using a fluorescence-quenching assay to detect inhibition of RAD52's ssDNA annealing activity.
• Characterized 70 putative inhibitors through biochemical assays.
• Evaluated inhibitor efficacy in cell-based assays, including assessing growth suppression in BRCA1- and BRCA2-deficient cells and inhibition of RAD52-dependent single-strand annealing (SSA) in human cells.

Main Results:

• Identified specific small molecule inhibitors that target RAD52's biochemical activities.
• Demonstrated that these compounds suppress the growth of BRCA1- and BRCA2-deficient cancer cells.
• Confirmed that the identified compounds inhibit RAD52-dependent SSA in human cells.

Conclusions:

• RAD52 is a viable target for cancer therapy development.
• The identified small molecules specifically inhibit RAD52's function and show potential in preclinical cancer models.
• These compounds can serve as tools to investigate DNA repair mechanisms and advance novel cancer treatments.