{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T09:58:17Z","timestamp":1781690297231,"version":"3.54.5"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":67,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","award":["A-19487"],"award-info":[{"award-number":["A-19487"]}],"id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Recent genetic studies have shown somatic expansion of the CAG repeat is the key process driving Huntington\u2019s disease (HD) pathogenesis. Recognition of insertion-deletion loops (IDLs), lesions prone to form within the CAG repeat, by Muts\u03b2 (MSH3\/MSH2) is thought to be the primary event in the expansion process. This starts a cascade that leads to error-prone repair and incorporation of additional CAG units into the repeat. In vitro data shows MSH3 binds IDLs through a DNA-binding pocket formed by MSH3 residues Y245\/K246. In this study, we investigated the significance of this DNA-binding motif in CAG repeat expansion using cell lines harbouring long, unstable HTT CAG repeats. Genetic disruption of the MSH3 Y245\/K246 motif significantly reduced DNA interaction, exhibited MMR deficiency in a frameshift mutator assay, and abrogated repeat expansion in a U2OS cell line expressing mutant HTT exon 1. Pharmacological blockade of this site using a small molecule targeting the DNA-binding pocket similarly reduced DNA binding and repeat expansion in a U2OS cell line. Crucially, this molecule also slowed CAG repeat expansion in medium spiny neurones derived from HD patient-iPSCs. Targeting of the MSH3 IDL binding pocket may represent a possible therapeutic strategy.<\/jats:p>","DOI":"10.1093\/narmme\/ugag031","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T11:43:19Z","timestamp":1780573399000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic or pharmacological disruption of the MSH3 Y245\/K246 IDL binding pocket slows CAG repeat expansion"],"prefix":"10.1093","volume":"3","author":[{"given":"Rob","family":"Goold","sequence":"first","affiliation":[{"name":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["United Kingdom"]},{"name":"Dementia Research Institute at UCL , London WC1N 3BG ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine","family":"Donaldson","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["United Kingdom"]},{"name":"Dementia Research Institute at UCL , London WC1N 3BG ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Gidney","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["United Kingdom"]},{"name":"Dementia Research Institute at UCL , London WC1N 3BG ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Goff","sequence":"additional","affiliation":[{"name":"Huntington\u2019s Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["United 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