{"doi":"10.1093/nar/gkab785","title":"XAB2 promotes Ku eviction from single-ended DNA double-strand breaks independently of the ATM kinase","abstract":"<jats:title>Abstract</jats:title><jats:p>Replication-associated single-ended DNA double-strand breaks (seDSBs) are repaired predominantly through RAD51-mediated homologous recombination (HR). Removal of the non-homologous end-joining (NHEJ) factor Ku from resected seDSB ends is crucial for HR. The coordinated actions of MRE11-CtIP nuclease activities orchestrated by ATM define one pathway for Ku eviction. Here, we identify the pre-mRNA splicing protein XAB2 as a factor required for resistance to seDSBs induced by the chemotherapeutic alkylator temozolomide. Moreover, we show that XAB2 prevents Ku retention and abortive HR at seDSBs induced by temozolomide and camptothecin, via a pathway that operates in parallel to the ATM-CtIP-MRE11 axis. Although XAB2 depletion preserved RAD51 focus formation, the resulting RAD51-ssDNA associations were unproductive, leading to increased NHEJ engagement in S/G2 and genetic instability. Overexpression of RAD51 or RAD52 rescued the XAB2 defects and XAB2 loss was synthetically lethal with RAD52 inhibition, providing potential perspectives in cancer therapy.</jats:p>","journal":"Nucleic Acids Research","year":2021,"id":42045,"datarank":0.5953190662410207,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.19946046679873183,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.19946046679873183,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":10,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":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":201767,"name":"Hélène Erasimus","orcid":null,"position":1,"is_corresponding":false},{"id":201768,"name":"Lia Pinto","orcid":null,"position":2,"is_corresponding":false},{"id":201769,"name":"Marie-Christine Caron","orcid":null,"position":3,"is_corresponding":false},{"id":201770,"name":"Diyavarshini Gopaul","orcid":null,"position":4,"is_corresponding":false},{"id":201771,"name":"Thibaut Peterlini","orcid":null,"position":5,"is_corresponding":false},{"id":201772,"name":"Katrin Neumann","orcid":null,"position":6,"is_corresponding":false},{"id":201773,"name":"Petr V Nazarov","orcid":"0000-0003-3443-0298","position":7,"is_corresponding":false},{"id":201774,"name":"Sabrina Fritah","orcid":null,"position":8,"is_corresponding":false},{"id":201775,"name":"Barbara Klink","orcid":null,"position":9,"is_corresponding":false},{"id":201776,"name":"Christel C Herold-Mende","orcid":null,"position":10,"is_corresponding":false},{"id":201777,"name":"Simone P Niclou","orcid":null,"position":11,"is_corresponding":false},{"id":201778,"name":"Philippe Pasero","orcid":null,"position":12,"is_corresponding":false},{"id":189229,"name":"Patrick Calsou","orcid":"0000-0001-7951-9806","position":13,"is_corresponding":false},{"id":201482,"name":"Jean-Yves Masson","orcid":null,"position":14,"is_corresponding":false},{"id":201779,"name":"Sébastien Britton","orcid":"0000-0002-7008-5316","position":15,"is_corresponding":false},{"id":201780,"name":"Eric Van Dyck","orcid":"0000-0001-8614-2402","position":16,"is_corresponding":false},{"id":201766,"name":"Abhishek Bharadwaj Sharma","orcid":"0000-0003-2554-1025","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":2.639057329615259,"endowment":2.639057329615259,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"34500463","pmcid":"PMC8464071","openalex_id":"https://openalex.org/W3196359758","authors":[],"funders":[{"funder_name":"Fonds National de la Recherche Luxembourg","grant_id":"7.4503.11","title":null},{"funder_name":"Fonds National de la Recherche Luxembourg","grant_id":"7.4633.16","title":null},{"funder_name":"Canadian Institutes of Health Research","grant_id":"FDN388879","title":null},{"funder_name":"Canadian Institutes of Health Research","grant_id":"unidentified","title":"unidentified"},{"funder_name":"Doctoral School for Systems and Molecular Biomedicine, University of Luxembourg","grant_id":"","title":null},{"funder_name":"Télévie/Fonds National de la Recherche","grant_id":"","title":null},{"funder_name":"Fondation Recherche Médicale","grant_id":"","title":null},{"funder_name":"Ligue Nationale Contre le Cancer","grant_id":"","title":null}],"total_grants":8,"fwci":0.8955,"citation_percentile":0.73028565,"influential_citations":1,"citation_trend":[{"year":2021,"count":2},{"year":2022,"count":2},{"year":2023,"count":2},{"year":2024,"count":5},{"year":2025,"count":1},{"year":2026,"count":1}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://academic.oup.com/nar/article-pdf/49/17/9906/40439248/gkab785.pdf","host_type":"journal"},{"url":"https://academic.oup.com/nar/article-pdf/49/17/9906/40439248/gkab785.pdf","host_type":"GOLD"},{"url":"https://academic.oup.com/nar/article-pdf/49/17/9906/40439248/gkab785.pdf","host_type":"publisher"},{"url":"http://academic.oup.com/nar/article-pdf/49/17/9906/40439248/gkab785.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/nar/gkab785","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/34500463","host_type":"repository"},{"url":"https://hdl.handle.net/11250/2838433","host_type":"repository"},{"url":"https://hal.science/hal-03371180","host_type":"repository"},{"url":"http://europepmc.org/pmc/articles/PMC8464071","host_type":"repository"},{"url":"https://orbilu.uni.lu/handle/10993/60431","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8464071","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC8464071","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8464071?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1093/nar/gkab785","host_type":""},{"url":"https://dx.doi.org/10.1093/nar/gkab785","host_type":""},{"url":"https://orbilu.uni.lu/bitstream/10993/60431/1/gkab785.pdf","host_type":""},{"url":"https://doi.org/https://doi.org/10.1093/nar/gkab785","host_type":""}],"fields_of_study":["DNA Repair Mechanisms","PARP inhibition in cancer therapy","Cancer therapeutics and mechanisms","Medicine","Biology","0301 basic medicine","0303 health sciences","03 medical and health sciences","Alkylating Agents","Ataxia Telangiectasia Mutated Proteins","Camptothecin","Cell Line, Tumor","DNA Breaks, Double-Stranded","DNA End-Joining Repair","Endodeoxyribonucleases","Glioblastoma","Homologous Recombination","Humans","Ku Autoantigen","MRE11 Homologue Protein","RNA Interference","RNA Splicing Factors","RNA, Small Interfering","Rad51 Recombinase","Rad52 DNA Repair and Recombination Protein","Temozolomide"],"mesh_terms":["Ku Autoantigen","RNA Splicing Factors","MRE11 Homologue Protein","Temozolomide","Alkylating Agents","Camptothecin","Endodeoxyribonucleases","Glioblastoma","Humans","RNA Interference","RNA, Small Interfering","Cell Line, Tumor","Rad51 Recombinase","Rad52 DNA Repair and Recombination Protein","DNA Breaks, Double-Stranded","Homologous Recombination","DNA End-Joining Repair","Ataxia Telangiectasia Mutated Proteins"],"keywords":["RAD51","Biology","Non-homologous end joining","Homologous recombination","RAD52","DNA damage","Ku80","Genome instability","Nuclease","DNA repair","Molecular biology","DNA","DNA repair protein XRCC4","Homologous chromosome","Cell biology","Genetics","DNA-binding protein","Nucleotide excision repair","Gene","Transcription factor","DNA End-Joining Repair","Ataxia Telangiectasia Mutated Proteins/metabolism","EC 2.7.11.1 (ATM protein, human)","Oncologie","Ataxia Telangiectasia Mutated Proteins","Genome Integrity, Repair and Replication","RAD52 protein, human","Temozolomide/adverse effects/pharmacology","Rad51 Recombinase/metabolism","DNA Breaks, Double-Stranded","Human health sciences","RNA, Small Interfering","Camptothecin/adverse effects/pharmacology","DNA End-Joining Repair/genetics","RNA, Small Interfering/genetics","XT3Z54Z28A (Camptothecin)","MRE11 Homologue Protein","MRE11 protein, human","EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)","Glioblastoma/drug therapy","XAB2 protein, human","EC 2.7.7.- (Rad51 Recombinase)","Oncology","EC 2.7.7.- (RAD51 protein, human)","RNA Interference","RNA Splicing Factors","EC 3.1.- (Endodeoxyribonucleases)","570","Alkylating Agents","EC 3.6.4.12 (XRCC5 protein, human)","610","Sciences de la santé humaine","Rad52 DNA Repair and Recombination Protein/metabolism","Cell Line, Tumor","Temozolomide","Humans","Ku Autoantigen","Endodeoxyribonucleases","RNA Splicing Factors/genetics/metabolism","EC 3.1.- (RBBP8 protein, human)","Rad52 DNA Repair and Recombination Protein","EC 4.2.99.- (Ku Autoantigen)","Endodeoxyribonucleases/metabolism","YF1K15M17Y (Temozolomide)","Ku Autoantigen/metabolism","Alkylating Agents/adverse effects/pharmacology","Homologous Recombination/genetics","Camptothecin","Rad51 Recombinase","MRE11 Homologue Protein/metabolism","Glioblastoma","EC 3.1.- (MRE11 Homologue Protein)"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-13T19:10:25.806927Z","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":[]}