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

• Type: Article in International Scientific Journal
• Date: 2004

Authors

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

Journal

Title: Journal of Biological Chemistry

Vol. 279

ISSN: 0021-9258

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 81 Citations

Scopus - 67 Citations

Other information

Authenticus ID: 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11