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Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1), is caused by the homozygous H493R mutation in tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme that initiates the repair of DNA topoisomerase 1 (TOP1)-induced SSBs by unlinking the TOP1 peptide from the break. Although TDP1 also initiates the repair of TOP1-induced DNA double-strand breaks (DSBs) associated with transcription, the role of TOP1-induced DSBs in SCAN1 pathology remains unclear. Here, we have addressed the impact of the SCAN1\/H493R mutation on the repair of TOP1-induced DSBs. We demonstrate that while TDP1 loss delays the repair of these breaks, SCAN1\/H493R completely blocks it in RPE-1 quiescent cells. This blockage is specific to DSBs and is accompanied by a prolonged trapping of mutated TDP1 on DNA, but not of TOP1 cleavage complexes (TOP1cc). Intriguingly, the H263A inactivating mutation of TDP1, which accumulates TOP1cc, also blocks TOP1-induced DSB repair. Importantly, both SCAN1\/H493R and H263A mutations exhibit genome instability and cell death. Moreover, we demonstrate that tyrosyl-DNA phosphodiesterase 2 (TDP2) can compensate for TDP1 loss in RPE-1 quiescent cells. Collectively, our data support the potential role of TOP1-induced DSBs as a main contributor to certain hereditary neurological syndromes.<\/jats:p>","DOI":"10.1038\/s41419-025-08085-y","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T14:49:44Z","timestamp":1764341384000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["H263A and SCAN1\/H493R mutant TDP1 block TOP1-induced double-strand break repair during gene transcription in quiescent cells and promote cell death"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4828-4906","authenticated-orcid":false,"given":"Diana","family":"Rubio-Contreras","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6651-3637","authenticated-orcid":false,"given":"Daniel","family":"Hidalgo-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Angulo-Jim\u00e9nez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esperanza","family":"Granado-Calle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarita","family":"Sabio-Bonilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose F.","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5693-3489","authenticated-orcid":false,"given":"Fernando","family":"G\u00f3mez-Herreros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"8085_CR1","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1038\/nrm.2016.111","volume":"17","author":"Y Pommier","year":"2016","unstructured":"Pommier Y, Sun Y, Huang S-YN, Nitiss JL. 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