{"doi":"10.1016/j.celrep.2025.116386","title":"Break-induced replication is activated to repair R-loop-associated double-strand breaks in SETX-deficient cells","abstract":"The primary role of break-induced replication (BIR) is to repair single-ended double-strand breaks (seDSBs) generated at broken replication forks and eroding telomeres. In this study, we demonstrated that when senataxin (SETX), an RNA/DNA helicase, is defective, hyper-recombination using the BIR mechanism is induced at R-loops/hybrid-accumulated double-ended DSBs (deDSBs), uncovering a role for BIR in the repair of R-loops/hybrids-associated deDSBs. Intriguingly, the loss of SETX not only triggers non-canonical hyper-end resection requiring RAD52 and XPF but also stalls Polα-primase-initiated end-fill DNA synthesis due to the accumulation of RNA/DNA hybrids on single-strand DNA (ssDNA) overhangs at deDSBs. This conflict between fill-in DNA synthesis and accumulated hybrids induces PCNA ubiquitination and PIF1 loading, thereby initiating the BIR mechanism at deDSBs. Hyper-resection further enhances PCNA ubiquitination and PIF1 loading, driving BIR-mediated hyper-recombination. Moreover, dysfunctional SETX is synthetic lethal with loss of PIF1, RAD52, or XPF, offering new strategies for targeted treatment of SETX-deficient tumors.","journal":"Cell Reports","year":2025,"id":524576,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9539,"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":1117230,"name":"Youhang Li","orcid":"0009-0003-8128-0154","position":1,"is_corresponding":false},{"id":1398122,"name":"Yuqin Zhao","orcid":"0009-0000-1656-110X","position":2,"is_corresponding":false},{"id":449443,"name":"Sameer Bikram Shah","orcid":"0000-0001-9442-0054","position":3,"is_corresponding":false},{"id":417471,"name":"Linda Shi","orcid":"0000-0002-2444-367X","position":4,"is_corresponding":false},{"id":323835,"name":"Xiaohua Wu","orcid":"0000-0003-4947-3047","position":5,"is_corresponding":false},{"id":1253713,"name":"Tonghai Wu","orcid":"0000-0003-1277-7848","position":0,"is_corresponding":true}],"reference_count":110,"raw_metadata":null,"created_at":"2026-07-19T02:50:12.083054Z","pmid":"41037402","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":[]}