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Measurement of mRNA Decay Rates in Saccharomyces cerevisiae Using rpb1-1 Strains
Published on: December 13, 2014
New insights into the interplay between the translation machinery and nonsense-mediated mRNA decay factors
Etienne Raimondeau1, Joshua C Bufton2, Christiane Schaffitzel3
1European Molecular Biology Laboratory, 71 Avenue des Martyrs, 38042 Grenoble, France.
Abstract:
Faulty mRNAs with a premature stop codon (PTC) are recognized and degraded by nonsense-mediated mRNA decay (NMD). Recognition of a nonsense mRNA depends on translation and on the presence of NMD-enhancing or the absence of NMD-inhibiting factors in the 3'-untranslated region. Our review summarizes our current understanding of the molecular function of the conserved NMD factors UPF3B and UPF1, and of the anti-NMD factor Poly(A)-binding protein, and their interactions with ribosomes translating PTC-containing mRNAs. Our recent discovery that UPF3B interferes with human translation termination and enhances ribosome dissociation in vitro, whereas UPF1 is inactive in these assays, suggests a re-interpretation of previous experiments and modification of prevalent NMD models. Moreover, we discuss recent work suggesting new functions of the key NMD factor UPF1 in ribosome recycling, inhibition of translation re-initiation and nascent chain ubiquitylation. These new findings suggest that the interplay of UPF proteins with the translation machinery is more intricate than previously appreciated, and that this interplay quality-controls the efficiency of termination, ribosome recycling and translation re-initiation.
Insights
Nonsense-mediated mRNA decay (NMD) degrades faulty mRNAs. New research shows UPF3B protein interferes with translation termination, impacting NMD pathway models and revealing complex UPF protein roles in quality control.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Nonsense-mediated mRNA decay (NMD) is a crucial cellular surveillance pathway that eliminates aberrant messenger RNAs (mRNAs) containing premature termination codons (PTCs).
- NMD efficiency is modulated by regulatory factors within the 3'-untranslated region (3'-UTR) of mRNAs, including NMD enhancers and inhibitors.
- The conserved UPF proteins (UPF1, UPF2, UPF3A/B) are central components of the NMD machinery, interacting with translation and RNA-processing factors.
Purpose of the Study:
- To review and synthesize current knowledge on the molecular functions of UPF3B, UPF1, and Poly(A)-binding protein (PABP) in NMD.
- To present recent findings on the interaction of these factors with translating ribosomes, particularly those carrying PTC-containing mRNAs.
- To propose modifications to existing NMD models based on new experimental evidence regarding UPF3B and UPF1 activities.
Main Methods:
- In vitro biochemical assays to study the interaction of UPF3B and UPF1 with translating ribosomes.
- Analysis of ribosome dissociation and translation termination efficiency.
- Review and integration of recent published research on NMD factors and their functions.
Main Results:
- UPF3B was found to interfere with human translation termination and enhance ribosome dissociation in vitro.
- UPF1 showed no significant activity in these specific in vitro translation termination assays.
- Recent studies suggest novel roles for UPF1 in ribosome recycling, translation re-initiation inhibition, and nascent polypeptide ubiquitylation.
Conclusions:
- The interplay between UPF proteins and the translation machinery is more complex than previously understood.
- UPF3B's direct interference with translation termination challenges existing NMD models.
- These intricate interactions are critical for quality control of mRNA translation, including termination efficiency, ribosome recycling, and translation re-initiation.
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