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

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

http://hdl.handle.net/10362/24286

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Autores

Pereira, Francisco J C

Teixeira, Alexandre R. S.

Liebhaber, Stephen A.

Romão, Luísa

Resumo(s)

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.

Descrição

Fundacao para a Ciencia e a Tecnologia (FCT) [POCI/BIA-BCM/59140/2004 and UID/MULTI/04046/2013 to BioISI from FCT/MCTES/PIDDAC; SFRH/BD/14273/2003 to F.J.C.P. and SFRH/BD/63581/2009 to C.B.]. Funding for open access charge: Instituto Nacional de Saude Doutor Ricardo Jorge and Oxford Journals Publisher.