{"doi":"10.1126/sciadv.ady7028","title":"Topoisomerase III-beta protects from immune dysregulation and tumorigenesis","abstract":"Topoisomerase III-beta (Top3b) reduces nucleic acid torsional stress and intertwining generated during RNA and DNA metabolism while protecting the genome from pathological R-loops, which otherwise result in DNA breakage and genome instability. By studying Top3b knockout mice ( Top3b -KO), we find that the loss of Top3b accelerates the development of spontaneous atypical lymphoid hyperplasia and lymphomas arising in spleens and lymph nodes, organs with prominent Top3b expression. Aging Top3b -KO mice also display splenomegaly and systemic immune alterations including neutrophilia and lymphopenia consistent with chronic inflammation. At the molecular level, Top3b deficiency causes genome-wide R-loop accumulation in splenocytes as measured by CUT&Tag sequencing. Increased R-loops are associated with genomic breaks and activation of immune signaling pathways including innate and adaptive immune cell signaling, IL-4 signaling, FAK signaling, and cGAS-STING. In addition, knocking-out Top3b promotes the rapid development of syngeneic EL4 T cell lymphomas. In conclusion, our work implies that Top3b protects from lymphoma, tumorigenesis, and immune dysregulations.","journal":"Science Advances","year":2025,"id":535828,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"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":349660,"name":"Simone A. Baechler","orcid":null,"position":1,"is_corresponding":false},{"id":770678,"name":"Anjali Dhall","orcid":"0000-0002-0400-2084","position":2,"is_corresponding":false},{"id":1077037,"name":"Sourav Saha","orcid":"0000-0002-0854-5991","position":3,"is_corresponding":false},{"id":1420040,"name":"Hongliang Zhang","orcid":"0000-0002-2834-4839","position":4,"is_corresponding":false},{"id":658614,"name":"Laura Bassel","orcid":"0000-0003-1684-6839","position":5,"is_corresponding":false},{"id":447794,"name":"Shuling Zhang","orcid":"0009-0006-4314-9691","position":6,"is_corresponding":false},{"id":268299,"name":"Min-Jung Lee","orcid":"0000-0003-3943-8133","position":7,"is_corresponding":false},{"id":1208614,"name":"N Sato","orcid":"0009-0007-1772-3183","position":8,"is_corresponding":false},{"id":812530,"name":"Shraddha Rastogi","orcid":"0000-0003-0680-0407","position":9,"is_corresponding":false},{"id":563306,"name":"Suresh Kumar","orcid":"0000-0001-7404-8259","position":10,"is_corresponding":false},{"id":637532,"name":"Muhammad S. Alam","orcid":null,"position":11,"is_corresponding":false},{"id":278617,"name":"Liton Kumar Saha","orcid":"0000-0003-3391-280X","position":12,"is_corresponding":false},{"id":378675,"name":"Beverly A. Mock","orcid":"0000-0003-2479-4549","position":13,"is_corresponding":false},{"id":485523,"name":"Valentina M. Factor","orcid":null,"position":14,"is_corresponding":false},{"id":232027,"name":"Yves Pommier","orcid":"0000-0002-3108-0758","position":15,"is_corresponding":false},{"id":941003,"name":"Md Rasel Al Mahmud","orcid":"0000-0003-0401-3311","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-19T02:52:00.885532Z","pmid":"41417894","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":[]}