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One approach to combat nonsense-related diseases relies on the use of engineered suppressor transfer RNAs (sup-tRNAs) that facilitate translational stop codon readthrough, thereby restoring full-length protein synthesis. While several sup-tRNAs have shown promising results in preclinical models, many exhibit low PTC suppression efficiency, precluding their use as therapeutics. For example, glutamic acid (Glu) codons represent one of the most common sites for nonsense mutations, yet existing sup-tRNAs are ineffective at suppressing Glu-to-Stop mutations. To address this limitation, here we describe a rationally designed sup-tRNA (tRNAGluV13) with greatly improved ability to suppress PTCs occurring at Glu codons. We demonstrate that tRNAGluV13 efficiently restores protein synthesis from multiple nonsense-containing reporter genes, faithfully installing Glu in response to PTCs. Additionally, we demonstrate that tRNAGluV13 can functionally rescue pathogenic PTCs that cause hereditary breast and ovarian cancer syndrome and cystic fibrosis. The ability of tRNAGluV13 to effectively suppress one of the most common PTC mutations should greatly expand the potential of sup-tRNA-based therapeutics.<\/jats:p>","DOI":"10.1093\/nar\/gkaf532","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T23:13:19Z","timestamp":1751065999000},"source":"Crossref","is-referenced-by-count":15,"title":["An engineered glutamic acid tRNA for efficient suppression of pathogenic nonsense mutations"],"prefix":"10.1093","volume":"53","author":[{"given":"Caitlin","family":"Specht","sequence":"first","affiliation":[{"name":"Indiana University School of Medicine Department of Biochemistry and Molecular Biology, , Indianapolis , IN 46202 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Tapia","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine Department of Microbiology and Immunology, , Indianapolis , IN 46202 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Penrod","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine Department of Pediatrics, , Indianapolis , IN 46202 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela A","family":"Soriano","sequence":"additional","affiliation":[{"name":"University of Connecticut School of Medicine Department of Molecular Biology and Biophysics, , Farmington , CT 06030 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Awawdeh","sequence":"additional","affiliation":[{"name":"University of Connecticut School of Medicine Department of Molecular Biology and Biophysics, , Farmington , CT 06030 ,","place":["United 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