A Small Molecule Screen Identifies an Inhibitor of DNA Repair Inducing the Degradation of TFIIH and the Chemosensitization of Tumor Cells to Platinum
Résumé
Nucleotide excision repair (NER) removes DNA lesions resulting from exposure to UV irradiation or chemical agents such as platinum-based drugs used as anticancer molecules. Pharmacological inhibition of NER is expected to enhance chemosensitivity but nontoxic NER inhibitors are rare. Using a drug repositioning approach, we identify spironolactone (SP), an antagonist of aldosterone, as a potent NER inhibitor. We found that SP promotes a rapid and reversible degradation of XPB, a subunit of transcription/repair factor TFIIH. Such degradation depends both on ubiquitin-activating enzyme and on the 26S proteasome. Supplementation of extracts from SP-treated cells with purified TFIIH restored TFIIH-dependent repair and transcription activities in vitro, demonstrating the specific impact of SP on two fundamental functions of TFIIH. Finally, SP potentiated the cytotoxicity of platinum derivatives toward tumor cells, making it a potential therapeutic and research tool.