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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,12,3]]},"abstract":"<jats:p>\n                    Over 50 hereditary degenerative disorders are caused by expansions of short tandem DNA repeats (STRs). (GAA)\n                    <jats:sub>n<\/jats:sub>\n                    repeat expansions are responsible for Friedreich\u2019s ataxia as well as late-onset cerebellar ataxias (LOCAs). Thus, the mechanisms of (GAA)\n                    <jats:sub>n<\/jats:sub>\n                    repeat expansions attract broad scientific attention. To investigate the role of DNA nicks in this process, we utilized a CRISPR-Cas9 nickase system to introduce targeted nicks adjacent to the (GAA)\n                    <jats:sub>n<\/jats:sub>\n                    repeat tract. We found that DNA nicks 5\u2032 of the (GAA)\n                    <jats:sub>100<\/jats:sub>\n                    run led to a dramatic increase in both the rate and scale of its expansion in dividing cells. Strikingly, they also promoted large-scale expansions of carrier- and large normal-size (GAA)\n                    <jats:sub>n<\/jats:sub>\n                    repeats, recreating, in a model system, the expansion events that occur in human pedigrees. DNA nicks 3\u2032 of the (GAA)\n                    <jats:sub>100<\/jats:sub>\n                    repeat led to a smaller but significant increase in the expansion rate as well. Our genetic analysis implies that in dividing cells, conversion of nicks into double-strand breaks (DSBs) during DNA replication followed by DSB or fork repair leads to repeat expansions. Finally, we showed that 5\u2032 GAA-strand nicks increase expansion frequency in nondividing yeast cells, albeit to a lesser extent than in dividing cells.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2413298121","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T15:00:38Z","timestamp":1732546838000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":13,"title":["Recurrent DNA nicks drive massive expansions of (GAA)\n                    <sub>n<\/sub>\n                    repeats"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8661-5837","authenticated-orcid":false,"given":"Liangzi","family":"Li","sequence":"first","affiliation":[{"name":"Department of Biology, Tufts University","place":["Medford"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6422-8735","authenticated-orcid":false,"given":"W. 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