{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T09:09:42Z","timestamp":1788944982884,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31871402"],"award-info":[{"award-number":["31871402"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Ovarian cancer is a lethal malignancy that frequently develops resistance to platinum\u2010based chemotherapies. Elucidating the genes that regulate DNA damage repair could lead to more effective treatments for ovarian cancer. Senataxin (SETX), an RNA\u2013DNA helicase, maintains R\u2010loop homeostasis to ensure replication fork progression, and its deficiency is linked to neurodegenerative diseases. However, its clinical relevance to solid tumors is not understood. We aimed to investigate the clinical significance and functional role of SETX in ovarian cancer progression and chemotherapy resistance. SETX expression was analyzed in ovarian cancer tissues, followed by CRISPR\u2013Cas9\u2010mediated knockout, mechanistic analyses, and RNASEH1 rescue experiments to investigate its role in ovarian cancer progression and chemoresistance. SETX was significantly overexpressed in ovarian tumors, and its high expression was correlated with cisplatin resistance and poor patient survival. SETX depletion significantly impaired tumor cell proliferation and invasion and sensitized cells to cisplatin\u2010induced apoptosis. Mechanistically, SETX deficiency triggered pathological R\u2010loop accumulation, which was accompanied by replication stress, DNA double\u2010strand breaks, and activation of DNA damage response. RNA\u2010seq analysis also revealed splicing alterations and U2AF1 interaction. Critically, R\u2010loop degradation induced by RNASEH1 overexpression rescued the DNA damage phenotype and growth defects induced by SETX loss. These findings reveal a dual oncogenic role for SETX. Maintaining R\u2010loop homeostasis supports malignant progression while conferring chemotherapy resistance. Therefore, SETX represents a promising therapeutic target, as its inhibition simultaneously suppresses tumor growth and overcomes chemotherapy resistance in ovarian cancer.<\/jats:p>","DOI":"10.1111\/cas.70520","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:55:08Z","timestamp":1788944108000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The\n                    <scp>DNA<\/scp>\n                    \/\n                    <scp>RNA<\/scp>\n                    Helicase\n                    <scp>SETX<\/scp>\n                    Maintains R\u2010Loop Homeostasis to Promote Chemoresistance in Ovarian Cancer"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6650-555X","authenticated-orcid":false,"given":"Zi\u2010Wei","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Cell Biology, College of Medicine Jiaxing University  Jiaxing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tu\u2010Nan","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science Zhejiang University of Technology  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi\u2010Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, College of Medicine Jiaxing University  Jiaxing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pathology First Affiliated Hospital of Jiaxing University\/The First Hospital of Jiaxing  Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duan\u2010Yong","family":"Feng","sequence":"additional","affiliation":[{"name":"College of Life Sciences and Medicine Zhejiang Sci\u2010Tech University  Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7128-8097","authenticated-orcid":false,"given":"Xiao\u2010Min","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, College of Medicine Jiaxing University  Jiaxing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Er\u2010Suo","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, College of Medicine Jiaxing University  Jiaxing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, College of Medicine Jiaxing University  Jiaxing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Min","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Jiaxing Hospital of Traditional Chinese Medicine  Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian\u2010Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Information Network and Artificial Intelligence, Jiaxing University  Jiaxing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Che","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Jiaxing Maternity and Child Health Care Hospital, Affiliated Women and Children Hospital Jiaxing University  Jiaxing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Wei","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, College of Medicine Jiaxing University  Jiaxing China"},{"name":"G60 STI Valley Industry and Innovation Institute Jiaxing University  Jiaxing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zha\u2010Jun","family":"Zhan","sequence":"additional","affiliation":[{"name":"Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Science Zhejiang University of Technology  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6760-7470","authenticated-orcid":false,"given":"Shu\u2010Qun","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital Second Military Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"issue":"1","key":"e_1_2_13_2_1","first-page":"17","article-title":"Cancer Statistics, 2023","volume":"73","author":"Siegel R. 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Molecular Cell Biology"},{"issue":"1","key":"e_1_2_13_12_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-17858-2","article-title":"Topoisomerase 1 Prevents Replication Stress at R\u2010Loop\u2010Enriched Transcription Termination Sites","volume":"11","author":"Promonet A.","year":"2020","journal-title":"Nature Communications"},{"issue":"1","key":"e_1_2_13_13_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-021-22830-9","article-title":"Single\u2010Molecule Imaging Reveals Replication Fork Coupled Formation of G\u2010Quadruplex Structures Hinders Local Replication Stress Signaling","volume":"12","author":"Lee W. T. 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L.","year":"2023","journal-title":"Nature Genetics"},{"issue":"6","key":"e_1_2_13_30_1","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1158\/0008-5472.CAN-23-1908","article-title":"AKT1 Interacts With DHX9 to Mitigate R Loop\u2010Induced Replication Stress in Ovarian Cancer","volume":"84","author":"Huang T. T.","year":"2024","journal-title":"Cancer Research"},{"issue":"8","key":"e_1_2_13_31_1","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.7150\/jca.72108","article-title":"ADAR1 Prevents R\u2010Loop Accumulation\u2010Driven ATR Pathway Activation in Ovarian Cancer","volume":"13","author":"Cui H.","year":"2022","journal-title":"Journal of Cancer"},{"issue":"21","key":"e_1_2_13_32_1","doi-asserted-by":"crossref","first-page":"11668","DOI":"10.1093\/nar\/gkad839","article-title":"ADAR1 Links R\u2010Loop Homeostasis to ATR Activation in Replication Stress Response","volume":"51","author":"Zhang B.","year":"2023","journal-title":"Nucleic Acids Research"},{"issue":"11","key":"e_1_2_13_33_1","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2415869122","article-title":"p53 Activates circASCC3 to Repress R\u2010Loops and Enhance Resistance to Chemotherapy","volume":"122","author":"Cao M.","year":"2025","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"1","key":"e_1_2_13_34_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2024.115142","article-title":"Transketolase Attenuates the Chemotherapy Sensitivity of Glioma Cells by Modulating R\u2010Loop Formation","volume":"44","author":"Fu M.","year":"2025","journal-title":"Cell Reports"},{"issue":"10","key":"e_1_2_13_35_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2025.116386","article-title":"Break\u2010Induced Replication Is Activated to Repair R\u2010Loop\u2010Associated Double\u2010Strand Breaks in SETX\u2010Deficient Cells","volume":"44","author":"Wu T.","year":"2025","journal-title":"Cell Reports"},{"issue":"1","key":"e_1_2_13_36_1","doi-asserted-by":"crossref","DOI":"10.1038\/s41392-021-00486-7","article-title":"Alternative Splicing and Cancer: A Systematic Review","volume":"6","author":"Zhang Y.","year":"2021","journal-title":"Signal Transduction and Targeted Therapy"},{"key":"e_1_2_13_37_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.drup.2025.101292","article-title":"Targeting CLK1\/SRSF7 Axis\u2010Dependent Alternative Splicing Sensitizes Pancreatic Ductal Adenocarcinoma to Chemotherapy and Immunotherapy","volume":"83","author":"Zhang C.","year":"2025","journal-title":"Drug Resistance Updates"},{"issue":"20","key":"e_1_2_13_38_1","doi-asserted-by":"crossref","first-page":"3894","DOI":"10.1158\/0008-5472.CAN-24-4233","article-title":"SRSF9 Forms Phase\u2010Separated Condensates to Promote Ovarian Cancer Progression by Inducing RNA Alternative Splicing That Is Inhibited by m6A Modification","volume":"85","author":"Zuo X.","year":"2025","journal-title":"Cancer Research"},{"issue":"6","key":"e_1_2_13_39_1","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/j.molcel.2022.02.025","article-title":"Precision Analysis of Mutant U2AF1 Activity Reveals Deployment of Stress Granules in Myeloid Malignancies","volume":"82","author":"Biancon G.","year":"2022","journal-title":"Molecular Cell"},{"issue":"6","key":"e_1_2_13_40_1","doi-asserted-by":"crossref","first-page":"21646","DOI":"10.1021\/jacs.3c08204","article-title":"Promoter R\u2010Loops Recruit U2AF1 to Modulate Its Phase Separation and RNA Splicing","volume":"145","author":"He X.","year":"2023","journal-title":"Journal of the American Chemical Society"},{"issue":"3","key":"e_1_2_13_41_1","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2306814121","article-title":"Activation of ER\u03b2 Hijacks the Splicing Machinery to Trigger R\u2010Loop Formation in Triple\u2010Negative Breast Cancer","volume":"121","author":"Wang D.","year":"2024","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"4","key":"e_1_2_13_42_1","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1158\/0008-5472.CAN-23-3239","article-title":"R\u2010Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription\u2010Replication Conflicts","volume":"84","author":"Liu Z. 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