Resistance of mRNAs with AUG-proximal nonsense mutations to nonsense-mediated decay reflects variables of mRNA structure and translational activity

Francisco J C Pereira, Alexandre R. S. Teixeira, Jian Kong, Cristina Barbosa, Ana Luísa Silva, Ana Marques-Ramos, Stephen A. Liebhaber, Luísa Romão

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Abstract

Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that recognizes and selectively degrades mRNAs carrying premature termination codons (PTCs). The level of sensitivity of a PTC-containing mRNA to NMD is multifactorial. We have previously shown that human β-globin mRNAs carrying PTCs in close proximity to the translation initiation AUG codon escape NMD. This was called the 'AUG-proximity effect'. The present analysis of nonsense codons in the human α-globin mRNA illustrates that the determinants of the AUG-proximity effect are in fact quite complex, reflecting the ability of the ribosome to re-initiate translation 3′ to the PTC and the specific sequence and secondary structure of the translated ORF. These data support a model in which the time taken to translate the short ORF, impacted by distance, sequence, and structure, not only modulates translation re-initiation, but also impacts on the exact boundary of AUG-proximity protection from NMD.

Original languageEnglish
Pages (from-to)6528-6544
Number of pages17
JournalNucleic Acids Research
Volume43
Issue number13
DOIs
Publication statusPublished - 23 May 2015

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