• Specifically inhibits RAD51-mediated HR, diminishes IR-induced RAD51 foci and enhances proteasomal degradation of RAD51.• Single agent activity and enhances chemosensitivity to receptor tyrosine kinase and microtubule inhibitors in a broad spectrum of cancer cells by inducing synthetic lethality.• Overcomes CML drug resistance. IC50 = 12-16 μM. The gene discussed is RAD51; the disease is cancer.