The role of mRNA translation on nonsense-mediated decay inhibition of transcripts carrying a short open reading frame
Year: 2011
Type: dissertation
Abstract: Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that recognizes and rapidly degrades mRNAs containing premature termination codons (PTC). The unified model for NMD, proposes that the decision of NMD triggering is the outcome of the competition between the cytoplasmatic poly(A)-binding protein 1 (PABPC1) and the NMD effector UPF1 for the termination complex. Consequently, PTCs located far, in a linear sense, from the poly(A) tail and associated PABPC1 in mRNAs containing residual downstream exon junction complexes (EJCs) are expected to elicit NMD. Nevertheless, it has been reported that mRNAs containing PTCs in close proximity to the translation initiation codon (AUG-proximal PTCs) can substantially evade NMD. The work described in this thesis was focused on the mechanistic basis for this NMD resistance, exemplified by human β-globin transcripts carrying an AUG-proximal PTC. We demonstrated that translation termination at an AUG-proximal PTC lacks the ribosome stalling that is evident in an NMD-sensitive PTC. In fact, we have shown that the establishment of an efficient translation termination reaction at the AUG-proximal PTC is dependent on PABPC1 interaction with the initiation factor eIF4G and with the release factor eRF3 at the terminating ribosome. These interactions underlie critical 3’-5’ linkage of translation initiation with efficient termination at the AUG-proximal PTC and contribute to an NMD-resistant PTC definition at an early phase of translation elongation. Furthermore, we provide strong evidence that the eukaryotic initiation factor 3 is involved in delivering eIF4G-associated PABPC1 into the vicinity of the AUG-proximal PTC through eIF3h and eIF3f subunits. These data support the “AUG-proximity effect” as a major inhibitor of the NMD pathway. The work presented here corroborates a role for PABPC1 on NMD evasion of AUG-proximal transcripts and provides further insights into the mechanistic details of PTC definition and translation initiation.
Author: Isabel Peixeiro
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2256159309