{"doi":"10.1093/nar/gkz1219","title":"HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>The tumor suppressor BRCA2 is essential for homologous recombination (HR), replication fork stability and DNA interstrand crosslink (ICL) repair in vertebrates. We show that ectopic production of HSF2BP, a BRCA2-interacting protein required for meiotic HR during mouse spermatogenesis, in non-germline human cells acutely sensitize them to ICL-inducing agents (mitomycin C and cisplatin) and PARP inhibitors, resulting in a phenotype characteristic of cells from Fanconi anemia (FA) patients. We biochemically recapitulate the suppression of ICL repair and establish that excess HSF2BP compromises HR by triggering the removal of BRCA2 from the ICL site and thereby preventing the loading of RAD51. This establishes ectopic expression of a wild-type meiotic protein in the absence of any other protein-coding mutations as a new mechanism that can lead to an FA-like cellular phenotype. Naturally occurring elevated production of HSF2BP in tumors may be a source of cancer-promoting genomic instability and also a targetable vulnerability.</jats:p>","journal":"Nucleic Acids Research","year":2020,"id":651222,"datarank":0.5050943744979712,"base_score":3.367295829986474,"endowment":3.367295829986474,"self_citation_contribution":0.5050943744979712,"citation_network_contribution":0.0,"self_endowment_contribution":0.5050943744979712,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1698265,"name":"Inger Brandsma","orcid":null,"position":1,"is_corresponding":false},{"id":1698266,"name":"Sari E van Rossum-Fikkert","orcid":null,"position":2,"is_corresponding":false},{"id":1698268,"name":"Nicole Verkaik","orcid":null,"position":3,"is_corresponding":false},{"id":1698270,"name":"Anneke B Oostra","orcid":null,"position":4,"is_corresponding":false},{"id":1698272,"name":"Josephine C Dorsman","orcid":null,"position":5,"is_corresponding":false},{"id":1698274,"name":"Dik C van Gent","orcid":null,"position":6,"is_corresponding":false},{"id":1056557,"name":"Puck Knipscheer","orcid":"0000-0003-4198-0132","position":7,"is_corresponding":false},{"id":1314028,"name":"Roland Kanaar","orcid":"0000-0001-9364-8727","position":8,"is_corresponding":false},{"id":1698276,"name":"Alex N Zelensky","orcid":"0000-0002-2664-271X","position":9,"is_corresponding":false},{"id":529992,"name":"Koichi Sato","orcid":"0000-0001-6024-8532","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>The tumor suppressor BRCA2 is essential for homologous recombination (HR), replication fork stability and DNA interstrand crosslink (ICL) repair in vertebrates. We show that ectopic production of HSF2BP, a BRCA2-interacting protein required for meiotic HR during mouse spermatogenesis, in non-germline human cells acutely sensitize them to ICL-inducing agents (mitomycin C and cisplatin) and PARP inhibitors, resulting in a phenotype characteristic of cells from Fanconi anemia (FA) patients. We biochemically recapitulate the suppression of ICL repair and establish that excess HSF2BP compromises HR by triggering the removal of BRCA2 from the ICL site and thereby preventing the loading of RAD51. This establishes ectopic expression of a wild-type meiotic protein in the absence of any other protein-coding mutations as a new mechanism that can lead to an FA-like cellular phenotype. Naturally occurring elevated production of HSF2BP in tumors may be a source of cancer-promoting genomic instability and also a targetable vulnerability.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19162232","pmcid":null,"openalex_id":null,"authors":[],"funders":[{"funder_name":"Netherlands Organization for Scientific Research","grant_id":"VIDI 700.10.421","title":null},{"funder_name":"Dutch Cancer Society","grant_id":"KWF HUBR 2015-7736","title":null},{"funder_name":"Dutch Cancer Society","grant_id":"EMCR 2008-4045","title":null},{"funder_name":"EC Seventh Framework Programm","grant_id":"FP7/2007-2013","title":null},{"funder_name":"EC Seventh Framework Programm","grant_id":"HEALTH-F2-2010-259893","title":null},{"funder_name":"Netherlands Organisation for Scientific Research (NWO)","grant_id":"700.10.421","title":"The molecular basis of Fanconi anemia pathway mediated DNA interstrand crosslink repair"},{"funder_name":"European Commission","grant_id":"259893","title":"The DNA damage response and breast cancer"}],"total_grants":7,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by-nc","oa_locations":[{"url":"https://academic.oup.com/nar/article-pdf/48/5/2442/32740869/gkz1219.pdf","host_type":"publisher"},{"url":"http://academic.oup.com/nar/article-pdf/48/5/2442/32740869/gkz1219.pdf","host_type":"publisher"},{"url":"https://pure.amsterdamumc.nl/ws/files/142050636/Hsf2bp-negatively-regulates-homologous-recombination-in-dna-interstrand-crosslink-repair.pdf","host_type":"repository"},{"url":"https://dspace.library.uu.nl/handle/1874/442169","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/7049687","host_type":"repository"},{"url":"https://pure.eur.nl/en/publications/4b3812ae-24c1-420c-a6f6-2cf2ed32f472","host_type":"repository"},{"url":"https://pure.knaw.nl/portal/en/publications/1d565756-fa77-430e-838a-9219dbda5e59","host_type":"repository"},{"url":"https://hdl.handle.net/20.500.11755/1d565756-fa77-430e-838a-9219dbda5e59","host_type":"repository"},{"url":"http://repub.eur.nl/pub/125359","host_type":"repository"},{"url":"https://research.vumc.nl/en/publications/3b689dfd-4411-494a-9def-64e00a99a48b","host_type":"repository"},{"url":"https://doi.org/10.1093/nar/gkz1219","host_type":""},{"url":"https://pubmed.ncbi.nlm.nih.gov/31960047","host_type":""},{"url":"http://dx.doi.org/10.1093/nar/gkz1219","host_type":""},{"url":"https://dx.doi.org/10.1093/nar/gkz1219","host_type":""},{"url":"https://www.scopus.com/pages/publications/85081075752","host_type":""},{"url":"https://pure.amsterdamumc.nl/en/publications/654297bd-09c4-4a52-9cf0-b7bce7f3454a","host_type":""}],"fields_of_study":["0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":[],"keywords":["BRCA2 Protein","DNA Repair","Xenopus","EMC OR-01","Cell Cycle Proteins","Genome Integrity, Repair and Replication","Cell Line","Mice","Fanconi Anemia","Proteolysis","Animals","Humans","EMC MGC-01-12-03","Rad51 Recombinase","Carrier Proteins","Homologous Recombination","Heat-Shock Proteins","DNA Damage","Protein Binding"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T06:52:09.241191Z","pmid":null,"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":[]}