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Selective killing of homologous recombination-deficient cancer cell lines by inhibitors of the RPA:RAD52 protein-protein interaction

PLoS ONE. 2021-03; 
Mona Al-Mugotir, Jeffrey J Lovelace, Joseph George, Mika Bessho, Dhananjaya Pal, Lucas Struble, Carol Kolar, Sandeep Rana, Amarnath Natarajan, Tadayoshi Bessho, Gloria E O Borgstahl
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摘要

Synthetic lethality is a successful strategy employed to develop selective chemotherapeutics against cancer cells. Inactivation of RAD52 is synthetically lethal to homologous recombination (HR) deficient cancer cell lines. Replication protein A (RPA) recruits RAD52 to repair sites, and the formation of this protein-protein complex is critical for RAD52 activity. To discover small molecules that inhibit the RPA:RAD52 protein-protein interaction (PPI), we screened chemical libraries with our newly developed Fluorescence-based protein-protein Interaction Assay (FluorIA). Eleven compounds were identified, including FDA-approved drugs (quinacrine, mitoxantrone, and doxorubicin). The FluorIA was used to rank the comp... More

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