{"doi":"10.1016/j.molcel.2025.10.026","title":"HSP90 buffers deleterious genetic variations in BRCA1","abstract":"Protein-folding chaperone heat shock protein 90 (HSP90) buffers genetic variation in diverse organisms, but the clinical significance of HSP90 buffering in human disease remains unclear. Here, we show that HSP90 buffers mutations in the BRCT domain of BRCA1. HSP90-buffered BRCA1 mutations result in protein variants that retain interactions with partner proteins and strongly rely on HSP90 for protein stability and function in cell survival. Moreover, HSP90-buffered BRCA1 variants confer poly (ADP-ribose) polymerase (PARP) inhibitor resistance in cancer cells. Low-level HSP90 inhibition overcomes this resistance, revealing a cryptic and mutant-specific HSP90-contingent synthetic lethality. Furthermore, by stabilizing metastable variants across the entirety of the BRCT domain, HSP90 reduces the clinical severity of BRCA1 mutations, allowing them to accumulate in populations. We estimate that HSP90 buffers 18% of known human BRCA1-BRCT missense mutations. Our work extends the clinical significance of HSP90 buffering to a prevalent class of variations in BRCA1 , pioneering its importance in therapy resistance and cancer predisposition. • HSP90 buffers mutations in BRCA1 by stabilizing the encoded protein variants • Low-level HSP90 inhibition reveals HSP90-buffered BRCA1 mutant phenotypes • HSP90-buffered BRCA1 mutations are prevalent across genomics databases • HSP90 modifies the clinical severity of BRCA1 mutations in cancer patients Gracia et al. show that HSP90 buffers BRCA1 mutations by stabilizing the encoded mutant proteins, promoting PARP inhibitor resistance. Low-level HSP90 inhibition selectively hypersensitizes HSP90-buffered BRCA1 mutant cancer cells to PARP inhibition. Carriers of HSP90-buffered BRCA1 mutations develop cancer roughly 10 years later than those with non-buffered mutations.","journal":"Molecular Cell","year":2025,"id":527556,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":463498,"name":"Xing-Han Zhang","orcid":"0000-0001-6994-5721","position":1,"is_corresponding":false},{"id":1192230,"name":"Patricia Montes","orcid":null,"position":2,"is_corresponding":false},{"id":1404315,"name":"Tin Chanh Pham","orcid":"0000-0002-9220-7070","position":3,"is_corresponding":false},{"id":694837,"name":"Min Huang","orcid":"0000-0002-9278-6594","position":4,"is_corresponding":false},{"id":323719,"name":"Junjie Chen","orcid":"0000-0002-1493-2189","position":5,"is_corresponding":false},{"id":965934,"name":"Georgios Ioannis Karras","orcid":"0000-0003-2933-1535","position":6,"is_corresponding":false},{"id":1191921,"name":"Brant Gracia","orcid":"0000-0002-2325-2126","position":0,"is_corresponding":true}],"reference_count":93,"raw_metadata":null,"created_at":"2026-07-19T02:50:39.280101Z","pmid":"41265458","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":[]}