{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:58:08Z","timestamp":1790211488335,"version":"4.1.0"},"reference-count":71,"publisher":"National Academy of Sciences","issue":"42","license":[{"start":{"date-parts":[[2020,3,30]],"date-time":"2020-03-30T00:00:00Z","timestamp":1585526400000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100003975","name":"Myotonic Dystrophy Foundation","doi-asserted-by":"publisher","award":["49"],"award-info":[{"award-number":["49"]}],"id":[{"id":"10.13039\/100003975","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["2016204076"],"award-info":[{"award-number":["2016204076"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,10,15]]},"abstract":"<jats:p>\n                    A CTG repeat expansion in the\n                    <jats:italic>DMPK<\/jats:italic>\n                    gene is the causative mutation of myotonic dystrophy type 1 (DM1). Transcription of the expanded CTG repeat produces toxic gain-of-function CUG RNA, leading to disease symptoms. A screening platform that targets production or stability of the toxic CUG RNA in a selective manner has the potential to provide new biological and therapeutic insights. A DM1 HeLa cell model was generated that stably expresses a toxic r(CUG)480 and an analogous r(CUG)0 control from\n                    <jats:italic>DMPK<\/jats:italic>\n                    and was used to measure the ratio-metric level of r(CUG)480 versus r(CUG)0. This DM1 HeLa model recapitulates pathogenic hallmarks of DM1, including CUG ribonuclear foci and missplicing of pre-mRNA targets of the muscleblind (MBNL) alternative splicing factors. Repeat-selective screening using this cell line led to the unexpected identification of multiple microtubule inhibitors as hits that selectively reduce r(CUG)480 levels and partially rescue MBNL-dependent missplicing. These results were validated by using the Food and Drug Administration-approved clinical microtubule inhibitor colchicine in DM1 mouse and primary patient cell models. The mechanism of action was found to involve selective reduced transcription of the CTG expansion that we hypothesize to involve the LINC (linker of nucleoskeleton and cytoskeleton) complex. The unanticipated identification of microtubule inhibitors as selective modulators of toxic CUG RNA opens research directions for this form of muscular dystrophy and may shed light on the biology of CTG repeat expansion and inform therapeutic avenues. This approach has the potential to identify modulators of expanded repeat-containing gene expression for over 30 microsatellite expansion disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1901893116","type":"journal-article","created":{"date-parts":[[2019,9,30]],"date-time":"2019-09-30T22:15:30Z","timestamp":1569881730000},"page":"20991-21000","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":34,"title":["A CTG repeat-selective chemical screen identifies microtubule inhibitors as selective modulators of toxic CUG RNA levels"],"prefix":"10.1073","volume":"116","author":[{"given":"Kaalak","family":"Reddy","sequence":"first","affiliation":[{"name":"Center for NeuroGenetics, University of Florida College of Medicine, Gainesville, FL 32610;"},{"name":"The RNA Institute, University at Albany, State University of New York, Albany, NY 12222;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana R.","family":"Jenquin","sequence":"additional","affiliation":[{"name":"Center for NeuroGenetics, University of Florida College of Medicine, Gainesville, FL 32610;"},{"name":"The RNA Institute, University at Albany, State University of New York, Albany, NY 12222;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ona L.","family":"McConnell","sequence":"additional","affiliation":[{"name":"Center for NeuroGenetics, University of Florida College of Medicine, Gainesville, FL 32610;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Cleary","sequence":"additional","affiliation":[{"name":"Center for NeuroGenetics, University of Florida College of Medicine, Gainesville, FL 32610;"},{"name":"The RNA Institute, University at Albany, State University of New York, Albany, NY 12222;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared I.","family":"Richardson","sequence":"additional","affiliation":[{"name":"Center for NeuroGenetics, University of Florida College of Medicine, Gainesville, FL 32610;"},{"name":"The RNA Institute, University at Albany, State University of New York, Albany, NY 12222;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda S.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Center for NeuroGenetics, University of Florida College of Medicine, Gainesville, FL 32610;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja C.","family":"Haerle","sequence":"additional","affiliation":[{"name":"Center for NeuroGenetics, University of Florida College of Medicine, Gainesville, FL 32610;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Delgado","sequence":"additional","affiliation":[{"name":"Center for NeuroGenetics, University of Florida College of Medicine, Gainesville, FL 32610;"},{"name":"Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori","family":"Planco","sequence":"additional","affiliation":[{"name":"Center for NeuroGenetics, University of Florida College of Medicine, Gainesville, FL 32610;"},{"name":"The RNA Institute, University at Albany, State University of New York, Albany, NY 12222;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4714-3044","authenticated-orcid":false,"given":"Masayuki","family":"Nakamori","sequence":"additional","affiliation":[{"name":"Department of Neurology, Osaka University Graduate School of Medicine, 565-0871 Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric T.","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for NeuroGenetics, University of Florida College of Medicine, Gainesville, FL 32610;"},{"name":"Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Andrew","family":"Berglund","sequence":"additional","affiliation":[{"name":"Center for NeuroGenetics, University of Florida College of Medicine, Gainesville, FL 32610;"},{"name":"The RNA Institute, University at Albany, State University of New York, Albany, NY 12222;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,9,30]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"385","article-title":"Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3\u2032 end of a transcript encoding a protein kinase family member","volume":"69","author":"Brook J. D.","year":"1992","unstructured":"J. D. Brook ., Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3\u2032 end of a transcript encoding a protein kinase family member. 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