{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T22:54:37Z","timestamp":1791500077762,"version":"4.3.4"},"posted":{"date-parts":[[2026,7,29]]},"group-title":"Neuroscience","reference-count":80,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["EHDN seed grant 1296"],"award-info":[{"award-number":["EHDN seed grant 1296"]}],"id":[{"id":"https:\/\/ror.org\/01wqpd686","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","award":["CNS2023-144738"],"award-info":[{"award-number":["CNS2023-144738"]}]},{"name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","award":["PID2024-159982OB-I00"],"award-info":[{"award-number":["PID2024-159982OB-I00"]}]},{"name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades","award":["PID2023-153168OB-I00"],"award-info":[{"award-number":["PID2023-153168OB-I00"]}]},{"name":"BC Children\u2018s Health Research Institute Investigator Grant Award"},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","award":["CIHR grant # ENG-191555"],"award-info":[{"award-number":["CIHR grant # ENG-191555"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001671","name":"Huntington\u2018s Disease Foundation","doi-asserted-by":"crossref","award":["1410890"],"award-info":[{"award-number":["1410890"]}],"id":[{"id":"10.13039\/100001671","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["NS126420"],"award-info":[{"award-number":["NS126420"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Dementia UK"},{"name":"Romanian Ministry of Research, Innovation, and Digitization","award":["PNRR-III-C9-2022-I8-66, contract 760114"],"award-info":[{"award-number":["PNRR-III-C9-2022-I8-66, contract 760114"]}]},{"id":[{"id":"https:\/\/ror.org\/046eh8t80","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,29]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Somatic instability (SI) of expanded DNA repeats is a hallmark of repeat expansion disorder (REDs) and drives onset and progression in Huntington\u2019s disease (HD) yet the absence of target engagement (TE) biomarkers for SI-modulating therapies represents a critical gap to clinical development. Here, we describe the development of the unscheduled repair synthesis assay (URSA)\u2014combining 5-ethynyl-2\u2019-deoxyuridine (EdU) pulse-labeling with digital PCR or sequencing\u2014and show that the CAG-expanded huntingtin (\n                  <jats:italic>HTT<\/jats:italic>\n                  ) exon 1 allele is a highly active DNA repair hotspot in cells from people with HD (PwHD). Repair activity increases with repeat length, is allele-specific, and depends strongly on MSH3, a central driver of somatic expansion. URSA robustly quantifies MSH3 modulation in preclinical models within days compared to weeks or months required by conventional repeat-length measurements. Critically, substantial repair activity is detectable in peripheral blood mononuclear cells (PBMCs) from PwHD, where signal correlates with CAG length and improves predictive models of somatic expansion (SE) beyond age and CAG length alone. Unlike repeat-length changes, which require years to accumulate in blood, URSA signal is measurable within days. These findings establish DNA repair activity at the mutant\n                  <jats:italic>HTT<\/jats:italic>\n                  locus as a mechanistically grounded pharmacodynamic biomarker, enabling TE monitoring on a clinically actionable timescale, and with broad applicability to REDs and other diseases where modulation of the DNA damage response is therapeutically targeted.\n                <\/jats:p>","DOI":"10.64898\/2026.07.29.741355","type":"posted-content","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T18:50:14Z","timestamp":1785351014000},"source":"Crossref","is-referenced-by-count":1,"title":["Unscheduled DNA synthesis reveals a DNA repair hotspot and biomarker of somatic instability at the expanded-CAG repeat tract in the huntingtin gene"],"prefix":"10.64898","author":[{"given":"Judith Praena","family":"Fernandez","sequence":"first","affiliation":[{"name":"Departament de Biomedicina, Facultat de Medicina i Ci\u00e8ncies de la Salut, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi I Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"G\u00e4rtner","sequence":"additional","affiliation":[{"name":"Evotec SE. Manfred Eigen Campus. Essener Bogen 7. 22419 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Perez-Perez","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain"},{"name":"Movement Disorders Unit, Sant Pau Hospital, Barcelona, Spain"},{"name":"Department of Medicine, Universitat Aut\u00f2noma de Barcelona (UAB), Barcelona, Spain"},{"name":"Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A.","family":"Cumming","sequence":"additional","affiliation":[{"name":"School of Molecular Biosciences, College of Medical, Veterinary and Life Scinces, University of Glasgow, Glasgow, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Djavad Mowafaghian Centre for Brain Health, Edwin S.H. Leong Centre for Healthy Aging, University of British Columbia, Vancouver, BC, Canada, British Columbia Children\u2019s Hospital Research Institute, University of British Columbia, Vancouver, V5Z 4H4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"van Belois","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Djavad Mowafaghian Centre for Brain Health, Edwin S.H. Leong Centre for Healthy Aging, University of British Columbia, Vancouver, BC, Canada, British Columbia Children\u2019s Hospital Research Institute, University of British Columbia, Vancouver, V5Z 4H4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangning","family":"He","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Kangning He, Denny Yang, Gabriel Balmus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denny","family":"Yang","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Kangning He, Denny Yang, Gabriel Balmus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Castells-Esteve","sequence":"additional","affiliation":[{"name":"Departament de Biomedicina, Facultat de Medicina i Ci\u00e8ncies de la Salut, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi I Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Berg\u00e9-Garde\u00f1es","sequence":"additional","affiliation":[{"name":"Departament de Biomedicina, Facultat de Medicina i Ci\u00e8ncies de la Salut, Institut de Neuroci\u00e8ncies, Universitat de Barcelona, Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi I Sunyer (IDIBAPS), Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna L.","family":"Bergander","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Medical Faculty, Ruhr University Bochum, Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof P.","family":"Lubieniecki","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Medical Faculty, Ruhr University Bochum, Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihai","family":"Micl\u0103u\u0219","sequence":"additional","affiliation":[{"name":"Department of Molecular Neuroscience, Transylvanian Institute of Neuroscience, Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Fissolo","sequence":"additional","affiliation":[{"name":"Servei de Neurologia and Centre d\u2019Esclerosi M\u00faltiple de Catalunya (Cemcat), Institut de Recerca Vall d\u2019Hebron (VHIR), Hospital Universitari Vall d\u2019Hebron, Universitat Aut\u00f2noma de Barcelona, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Comabella","sequence":"additional","affiliation":[{"name":"Servei de Neurologia and Centre d\u2019Esclerosi M\u00faltiple de Catalunya (Cemcat), Institut de Recerca Vall d\u2019Hebron (VHIR), Hospital Universitari Vall d\u2019Hebron, Universitat Aut\u00f2noma de Barcelona, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Vogt","sequence":"additional","affiliation":[{"name":"Evotec SE. Manfred Eigen Campus. Essener Bogen 7. 22419 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Gebauer","sequence":"additional","affiliation":[{"name":"Evotec SE. Manfred Eigen Campus. Essener Bogen 7. 22419 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Cavaleri","sequence":"additional","affiliation":[{"name":"Evotec SE. Manfred Eigen Campus. Essener Bogen 7. 22419 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin","family":"Voelkner","sequence":"additional","affiliation":[{"name":"Evotec SE. Manfred Eigen Campus. Essener Bogen 7. 22419 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Illarionova","sequence":"additional","affiliation":[{"name":"Evotec SE. Manfred Eigen Campus. 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