Nonsense mutations in close proximity to the initiation codon fail to trigger full nonsense-mediated mRNA decay

• Tipo: Artigo em Revista Científica Internacional
• Data: 2004

Autores

Inacio, A (Autor) Outra; Silva, AL (Autor) Outra; Pinto, J (Autor) Outra; Ji, XJ (Autor) Outra; Morgado, A (Autor) Outra; Almeida, F (Autor) Outra; Faustino, P (Autor) Outra; Lavinha, J (Autor) Outra; Liebhaber, SA (Autor) Outra; Romao, L (Autor) Outra

Revista

Título: Journal of Biological Chemistry

Vol. 279

ISSN: 0021-9258

Editora: Elsevier

Indexação

ISI Web of Knowledge - 81 Citações

Scopus - 67 Citações

Outras Informações

ID Authenticus: P-000-9CP

DOI: 10.1074/jbc.m405024200

Abstract (EN): Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that degrades mRNAs containing premature translation termination codons. In mammalian cells, a termination codon is ordinarily recognized as "premature" if it is located greater than 50-54 nucleotides 5' to the final exon-exon junction. We have described a set of naturally occurring human beta-globin gene mutations that apparently contradict this rule. The corresponding beta-thalassemia genes contain nonsense mutations within exon 1, and yet their encoded mRNAs accumulate to levels approaching wild-type beta-globin (beta(WT)) mRNA. In the present report we demonstrate that the stabilities of these mRNAs with nonsense mutations in exon 1 are intermediate between beta(WT) mRNA and beta-globin mRNA carrying a prototype NMD-sensitive mutation in exon 2 (codon 39 nonsense; beta39). Functional analyses of these mRNAs with 5'-proximal nonsense mutations demonstrate that their relative resistance to NMD does not reflect abnormal RNA splicing or translation re-initiation and is independent of promoter identity and erythroid specificity. Instead, the proximity of the nonsense codon to the translation initiation AUG constitutes a major determinant of NMD. Positioning a termination mutation at the 5' terminus of the coding region blunts mRNA destabilization, and this effect is dominant to the "50-54 nt boundary rule." These observations impact on current models of NMD.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 11