title: Binary specification of nonsense codons by splicing and cytoplasmic translation.
abstract: Premature translation termination codons resulting from nonsense or frameshift mutations are common causes of genetic disorders. Complications arising from the synthesis of C-terminally truncated polypeptides can be avoided by 'nonsense-mediated decay' of the mutant mRNAs. Premature termination codons in the beta-globin mRNA cause the common recessive form of beta-thalassemia when the affected mRNA is degraded, but the more severe dominant form when the mRNA escapes nonsense-mediated decay. We demonstrate that cells distinguish a premature termination codon within the beta-globin mRNA from the physiological translation termination codon by a two-step specification mechanism. According to the binary specification model proposed here, the positions of splice junctions are first tagged during splicing in the nucleus, defining a stop codon operationally as a premature termination codon by the presence of a 3' splicing tag. In the second step, cytoplasmic translation is required to validate the 3' splicing tag for decay of the mRNA. This model explains nonsense-mediated decay on the basis of conventional molecular mechanisms and allows us to propose a common principle for nonsense-mediated decay from yeast to man.
authors.affiliation: Department of Pediatrics, Charité-Virchow Medical Center, Humboldt University, Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Thermann
authors.forename: G
authors.initials: G
authors.lastname: Neu-Yilik
authors.forename: A
authors.initials: A
authors.lastname: Deters
authors.forename: U
authors.initials: U
authors.lastname: Frede
authors.forename: K
authors.initials: K
authors.lastname: Wehr
authors.forename: C
authors.initials: C
authors.lastname: Hagemeier
authors.forename: M W
authors.initials: MW
authors.lastname: Hentze
authors.forename: A E
authors.initials: AE
authors.lastname: Kulozik
mesh_terms: D018389:Codon, Nonsense / Q000235:genetics*; D018388:Codon, Terminator / Q000235:genetics; D019084:Fluorescent Antibody Technique, Indirect; D006367:HeLa Cells; D006801:Humans; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism*
chemical_list: D018389:Codon, Nonsense; D018388:Codon, Terminator; D012333:RNA, Messenger