title: Therapeutic suppression of premature termination codons: mechanisms and clinical considerations (review).
abstract: An estimated one-third of genetic disorders are the result of mutations that generate premature termination codons (PTCs) within protein coding genes. These disorders are phenotypically diverse and consist of diseases that affect both young and old individuals. Various small molecules have been identified that are capable of modulating the efficiency of translation termination, including select antibiotics of the aminoglycoside family and multiple novel synthetic molecules, including PTC124. Several of these agents have proved their effectiveness at promoting nonsense suppression in preclinical animal models, as well as in clinical trials. In addition, it has recently been shown that box H/ACA RNA-guided peudouridylation, when directed to modify PTCs, can also promote nonsense suppression. In this review, we summarize our current understanding of eukaryotic translation termination and discuss various methods for promoting the read-through of disease-causing PTCs, as well as the current obstacles that stand in the way of using the discussed agents broadly in clinical practice.
authors.affiliation: Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720, USA.
authors.forename: John
authors.initials: J
authors.lastname: Karijolich
authors.affiliation: Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Yi-Tao
authors.initials: YT
authors.lastname: Yu
mesh_terms: D000617:Aminoglycosides / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D018389:Codon, Nonsense / Q000037:antagonists & inhibitors / Q000235:genetics*; D030342:Genetic Diseases, Inborn / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009154:Mutation; D010069:Oxadiazoles / Q000627:therapeutic use*; D010443:Peptide Chain Termination, Translational; D020718:Ribonucleoproteins, Small Nucleolar / Q000235:genetics / Q000378:metabolism
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D018389:Codon, Nonsense; C485802:GAR1 protein, human; D010069:Oxadiazoles; D020718:Ribonucleoproteins, Small Nucleolar; C515878:ataluren