PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 16723977

Early nonsense: mRNA decay solves a translational problem.

Nadia Amrani·Matthew S Sachs·Allan Jacobson
View original source ↗Export metadata ↓

Abstract

Gene expression is highly accurate and rarely generates defective proteins. Several mechanisms ensure this fidelity, including specialized surveillance pathways that rid the cell of mRNAs that are incompletely processed or that lack complete open reading frames. One such mechanism, nonsense-mediated mRNA decay, is triggered when ribosomes encounter a premature translation-termination--or nonsense--codon. New evidence indicates that the specialized factors that are recruited for this process not only promote rapid mRNA degradation, but are also required to resolve a poorly dissociable termination complex.

Explore related subjects

3' Untranslated RegionsAnimalsCodon, NonsenseCodon, TerminatorProtein BiosynthesisRNA StabilityRNA, MessengerRibosomesTranscription, GeneticJournal ArticleResearch Support, N.I.H., ExtramuralReview

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Nadia Amrani, Matthew S Sachs, Allan Jacobson. 2006. Early nonsense: mRNA decay solves a translational problem.. https://doi.org/10.1038/nrm1942

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2026

A Conserved 3'UTR Stem-loop Directs UPF1/eIF4AIII-Dependent Regulation of GABARAPL1 mRNA.

RNA-binding proteins (RBP) interact with mRNA untranslated regions containing cis-regulatory elements to govern mRNA localization, stability, and translational efficiency. Among these trans-regulatory factors, RNA helicase UPF1 is a central factor which play a role in multiple mRNA decay pathways, including nonsense-mediated mRNA decay (NMD). NMD is triggered when an exon-junction complex (EJC) is located downstream of a premature termination codon. However, in some cases, NMD can be activated in an EJC-independent manner through mechanisms involving the 3'UTR. In the present study, we focused on the GABARAPL1 3'UTR, as previous studies had shown that this region plays a key role in NMD targeting, although the underlying molecular mechanism had not yet been elucidated. Unlike canonical NMD targets such as SC35, we found that the chemical inhibition of eIF4AIII helicase activity did not affect GABARAPL1 transcript levels, indicating that this transcript is regulated through its 3'UTR via an EJC-independent mechanism. We therefore investigated the potential presence of cis-regulatory element within the 3'UTR of GABARAPL1 which can regulate mRNA and protein levels in a UPF1-dependent manner. Furthermore, we identified a conserved RNA region spanning nucleotides 364-421 involved in GABARAPL1 targeting and used biochemical analysis to demonstrate the direct binding of UPF1 and eIF4AIII to this RNA region, to analyse its secondary structure in solution, and to map the protein-binding sites. By complementing these approaches with molecular modelling, we showed that this stem-loop adopts a stable global fold but a local flexibility and dynamic behaviour properties. Together, our results support the role of UPF1 and eIF4AIII as specific regulators of GABARAPL1 transcript and reveal a novel RNA regulatory element within its 3'UTR, which provides a completely unexpected binding site for these factors.

3' Untranslated Regions↗
PubMed2026

YIPFα1A expression is regulated by multilayered molecular mechanisms.

Yip domain family (YIPF) proteins are five-pass transmembrane proteins that localize primarily to the Golgi apparatus. These proteins assemble into higher-order complexes with each α-subunit pairing specifically with a β-subunit to form a dimer which then assemble into complexes with two to four dimers. Notably, β-subunit expression depends on the corresponding α-subunit partner, and conventional transient overexpression of α-subunits has been extremely inefficient, hindering deeper analysis of YIPF complexes. To identify the cause of poor exogenous expression, we examined YIPF gene features and found two properties correlated with low expression: (i) rare-codon enrichment in the CDS and (ii) extended 3' UTRs. Experimental analyses focusing on YIPFα1A revealed that rare-codon enrichment suppresses expression mainly at the mRNA level, consistent with translation-coupled mRNA decay, whereas inclusion of the native 3' UTR enhances expression by increasing mRNA abundance. Deletion mapping further showed that a proximal 3' UTR segment (51-150) is necessary and sufficient for mRNA stabilization, thereby elevating both mRNA and protein levels. Conversely, a distal 3' UTR fragment (1116-2230) increased mRNA but not protein levels, suggesting translational repression resulting in a reduced protein-to-mRNA ratio. Together, these findings explain the discrepancy between endogenous and exogenous YIPFα1A expression and propose a multilayered regulatory model in which rare codons decrease mRNA, the proximal 3' UTR stabilizes mRNA, and the distal 3' UTR reduces translation. Impact statement Our work advances YIPF biology and identifies post‑transcriptional mechanisms governing multi‑pass membrane proteins. We show rare‑codon and 3' UTR‑based control of trafficking proteins-an area largely unexplored-and introduce a new paradigm for membrane‑traffic regulation that will guide future studies of complex assembly, localization, and homeostasis.

3' Untranslated Regions↗
PubMed2017

MicroRNA‑27a promotes tumorigenesis via targeting AKT in triple negative breast cancer.

Altered microRNA (miRNA/miR) expression regulates tumor development and progression in triple‑negative breast cancer (TNBC). The present study examined the effect of miR‑27a on proliferation, migration and invasion of TNBC cells in vitro and in vivo. An MTT assay was performed to examine the proliferation of MDA‑MB‑231 and MDA‑MB‑468 breast cancer cells with either overexpression of miR‑27a or downregulation of miR‑27a, in the presence or absence of radiation. The migratory and invasive abilities of MDA‑MB‑231 and MDA‑MB‑468 breast cancer cells were assessed by Transwell migration and Matrigel invasion assays. The protein expression levels were examined by western blotting. The caspase‑Glo3/7 assay was performed to examine the effect of miR‑27a on radiation‑induced apoptosis in MDA‑MB‑231 and MDA‑MB‑468 breast cancer cells. A luciferase assay was performed to evaluate the effect of miR‑27a on phosphatase and tensin homolog (PTEN) and B cell lymphoma (Bcl)‑2 associated X, apoptosis regulator (BAX) expression. Immunodeficient nude mice were used to examine tumor growth following injection of MDA‑MB‑231 breast cancer cells. miR‑27a promoted proliferation in vitro and in vivo, and enhanced migration and invasion in TNBC cells. miR‑27a improved the survival of TNBC cells following irradiation. miR‑27a inhibited radiation‑induced apoptosis in TNBC cells by regulation of caspase 3/7 and Bcl‑2 expression. Furthermore, the expression levels of PTEN and phosphorylated protein kinase B in MDA‑MB‑231 and MDA‑MB‑468 cells was altered following overexpression of miR‑27a. The luciferase assay demonstrated that miR‑27a regulated PTEN and BAX expression by binding to 3'‑untranslated regions. Overall, miR‑27a exhibits an essential role in tumor development and progression in TNBC and may be used as a potential biomarker to predict radiotherapy response and prognosis for the disease.

3' Untranslated Regions↗