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While there is a significant depth of information on DNA damage repair, with many drugs and drug targets, most of this development has taken place in the context of cancer therapy. DNA damage repair in neurons does not rely on DNA replication correction mechanisms. However, there is a strong connection between DNA repair and neuronal metabolism, mediated by nucleotide salvaging and the poly ADP-ribose (PAR) response, and this connection has been implicated in other age-onset neurodegenerative diseases. Validation of leads including the mismatch repair protein MSH3, and interstrand cross-link repair protein FAN1, suggest the mechanism is driven by somatic CAG instability, which is supported by the protective effect of CAA substitutions in the CAG tract. We currently do not understand: how somatic instability is triggered; the state of DNA damage within expanding alleles in the brain; whether this damage induces mismatch repair and interstrand cross-link pathways; whether instability mediates toxicity, and how this relates to human ageing. We discuss DNA damage pathways uncovered by HD GWAS, known roles of other polyglutamine disease proteins in DNA damage repair, and a panel of hypotheses for pathogenic mechanisms.<\/jats:p>","DOI":"10.3233\/jhd-200414","type":"journal-article","created":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T21:01:40Z","timestamp":1612904500000},"page":"165-173","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":24,"title":["DNA Repair in Huntington\u2019s Disease and Spinocerebellar Ataxias: Somatic Instability and Alternative Hypotheses"],"prefix":"10.1177","volume":"10","author":[{"given":"Tamara","family":"Maiuri","sequence":"first","affiliation":[{"name":"McMaster University, Department of Biochemistry and Biomedical Sciences, Hamilton, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia L.K.","family":"Hung","sequence":"additional","affiliation":[{"name":"McMaster University, 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