{"doi":"10.1371/journal.pone.0248941","title":"Selective killing of homologous recombination-deficient cancer cell lines by inhibitors of the RPA:RAD52 protein-protein interaction","abstract":"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 compounds by their ability to inhibit the RPA:RAD52 PPI and showed mitoxantrone and doxorubicin to be the most effective. Initial studies using the three FDA-approved drugs showed selective killing of BRCA1-mutated breast cancer cells (HCC1937), BRCA2-mutated ovarian cancer cells (PE01), and BRCA1-mutated ovarian cancer cells (UWB1.289). It was noteworthy that selective killing was seen in cells known to be resistant to PARP inhibitors (HCC1937 and UWB1 SYr13). A cell-based double-strand break (DSB) repair assay indicated that mitoxantrone significantly suppressed RAD52-dependent single-strand annealing (SSA) and mitoxantrone treatment disrupted the RPA:RAD52 PPI in cells. Furthermore, mitoxantrone reduced radiation-induced foci-formation of RAD52 with no significant activity against RAD51 foci formation. The results indicate that the RPA:RAD52 PPI could be a therapeutic target for HR-deficient cancers. These data also suggest that RAD52 is one of the targets of mitoxantrone and related compounds.","journal":"PLoS ONE","year":2021,"id":175299,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9602,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":715834,"name":"Jeffrey J. Lovelace","orcid":"0000-0002-4217-8371","position":1,"is_corresponding":false},{"id":712125,"name":"Joseph W. George","orcid":null,"position":2,"is_corresponding":false},{"id":716361,"name":"Mika Bessho","orcid":null,"position":3,"is_corresponding":false},{"id":416601,"name":"Dhananjaya Pal","orcid":"0000-0001-7675-4819","position":4,"is_corresponding":false},{"id":715835,"name":"Lucas R. Struble","orcid":"0000-0002-0671-259X","position":5,"is_corresponding":false},{"id":715836,"name":"Carol Kolar","orcid":"0000-0003-1716-467X","position":6,"is_corresponding":false},{"id":415308,"name":"Sandeep Rana","orcid":"0000-0001-5802-5970","position":7,"is_corresponding":false},{"id":415310,"name":"Amarnath Natarajan","orcid":"0000-0001-5067-0203","position":8,"is_corresponding":false},{"id":309335,"name":"Tadayoshi Bessho","orcid":"0000-0001-8719-9646","position":9,"is_corresponding":false},{"id":655184,"name":"Gloria E. O. Borgstahl","orcid":"0000-0001-8070-0258","position":10,"is_corresponding":false},{"id":715833,"name":"Mona Al‐Mugotir","orcid":"0009-0006-9012-3531","position":0,"is_corresponding":true}],"reference_count":81,"raw_metadata":null,"created_at":"2026-07-18T23:47:11.249697Z","pmid":"33784323","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}