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Thus, the loss of TDP\u201043 dimerization may play a critical driving role in ALS pathogenesis, although its underlying mechanism remains unclear. In this study, the FokT (FokI\u2010TDP\u201043) system is developed, which fuses TDP\u201043 protein with FokI nuclease. By restoring TDP\u201043 dimerization, this system reactivates FokI nuclease activity, enabling the cleavage of DNA targets bound by TDP\u201043. Additionally, the FokT\u2010seq (FokT combined with genome\u2010wide unbiased identification of DNA double\u2010strand breaks enabled by sequencing, Guide\u2010seq) method is established, allowing genome\u2010wide detection of DNA sites bound by dimerized TDP\u201043. These findings reveal the essential role of TDP\u201043 dimerization in DNA binding, identify a series of related targets. Furthermore, this study offers a powerful tool for investigating dimerized transcription factors.<\/jats:p>","DOI":"10.1002\/advs.202508902","type":"journal-article","created":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T10:12:33Z","timestamp":1755943953000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dimer\u2010Specific FokT\u2010seq Reveals DNA\u2010Binding Dimerization and Novel Genomic Targets of TDP\u201043"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9161-9420","authenticated-orcid":false,"given":"Mingming","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry\/Hubei Province of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 China"},{"name":"Departmentof Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of Jiangsu,\u00a0Co\u2010innovation Center of Neuroregeneration Nantong University  Nantong 226001 China"},{"name":"Hubei Key Laboratory of Cognitive and Affective Disorders, Institute of Biomedical Sciences, School of Medicine Jianghan University  Wuhan 430056 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry\/Hubei Province of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruolan","family":"Yan","sequence":"additional","affiliation":[{"name":"Departmentof Biochemistry and Molecular Biology, School of Medicine, Key Laboratory of Neuroregeneration and Ministry of Education of 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