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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2017,3,28]]},"abstract":"<jats:p>\n                    Nonsense mutations underlie about 10% of rare genetic disease cases. They introduce a premature termination codon (PTC) and prevent the formation of full-length protein. Pharmaceutical gentamicin, a mixture of several related aminoglycosides, is a frequently used antibiotic in humans that can induce PTC readthrough and suppress nonsense mutations at high concentrations. However, testing of gentamicin in clinical trials has shown that safe doses of this drug produce weak and variable readthrough activity that is insufficient for use as therapy. In this study we show that the major components of pharmaceutical gentamicin lack PTC readthrough activity but the minor component gentamicin B1 (B1) is a potent readthrough inducer. Molecular dynamics simulations reveal the importance of ring I of B1 in establishing a ribosome configuration that permits pairing of a near-cognate complex at a PTC. B1 induced readthrough at all three nonsense codons in cultured cancer cells with\n                    <jats:italic>TP53<\/jats:italic>\n                    (tumor protein p53) mutations, in cells from patients with nonsense mutations in the\n                    <jats:italic>TPP1<\/jats:italic>\n                    (tripeptidyl peptidase 1),\n                    <jats:italic>DMD<\/jats:italic>\n                    (dystrophin),\n                    <jats:italic>SMARCAL1<\/jats:italic>\n                    (SWI\/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), and\n                    <jats:italic>COL7A1<\/jats:italic>\n                    (collagen type VII alpha 1 chain) genes, and in an in vivo tumor xenograft model. The B1 content of pharmaceutical gentamicin is highly variable and major gentamicins suppress the PTC readthrough activity of B1. Purified B1 provides a consistent and effective source of PTC readthrough activity to study the potential of nonsense suppression for treatment of rare genetic disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1620982114","type":"journal-article","created":{"date-parts":[[2017,3,13]],"date-time":"2017-03-13T21:09:36Z","timestamp":1489439376000},"page":"3479-3484","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":47,"title":["RETRACTED: Gentamicin B1 is a minor gentamicin component with major nonsense mutation suppression activity"],"prefix":"10.1073","volume":"114","author":[{"given":"Alireza","family":"Baradaran-Heravi","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Niesser","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aruna D.","family":"Balgi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunho","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Zimmerman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"South","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary J.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie C.","family":"Strynadka","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel B.","family":"Bally","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Roberge","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2017,3,13]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20763"},{"key":"e_1_3_3_2_2","unstructured":"; Electronic Medicines Compendium (2017) Gentamicin 10mg\/ml solution for injection or infusion. 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