Nonsense-mediated mRNA decay: from vacuum cleaner to Swiss army knife

Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Im Neuenheimer Feld 150, 69120 Heidelberg, Germany.
Genome biology (Impact Factor: 10.81). 02/2004; 5(4):218. DOI: 10.1186/gb-2004-5-4-218
Source: PubMed


Nonsense-mediated mRNA decay (NMD) downmodulates mRNAs that have in-frame premature termination codons and prevents translation of potentially harmful truncated proteins from aberrant mRNAs. Two new approaches have identified physiological NMD substrates, and suggest that NMD functions as a multipurpose tool in the modulation of gene expression.

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Available from: Gabriele Neu-Yilik
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    • "This complexity is necessary to generate the particular transcripts required for specific tissues or development stages. Some of the transcripts generated through AS seem not to be functional and are frequently removed by mechanisms such as nonsense mediated decay [9], [10]. By contrast, other transcripts perform their function as RNAs whereas others only fulfil their role when translated into proteins. "
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    ABSTRACT: Alternative splicing has the potential to increase the diversity of the transcriptome and proteome. Where more than one transcript arises from a gene they are often so different that they are quite unlikely to have the same function. However, it remains unclear if alternative splicing generally leads to a gene being involved in multiple biological processes or whether it alters the function within a single process. Knowing that genetic interactions occur between functionally related genes, we have used them as a proxy for functional versatility, and have analysed the sets of genes of two well-characterised model organisms: Caenorhabditis elegans and Drosophila melanogaster. Using network analyses we find that few genes are functionally homogenous (only involved in a few functionally-related biological processes). Moreover, there are differences between alternatively spliced genes and genes with a single transcript; specifically, genes with alternatively splicing are, on average, involved in more biological processes. Finally, we suggest that factors other than specific functional classes determine whether a gene is alternatively spliced.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "Moreover, many NMD factors are now known to have additional functions extending beyond NMD (reviewed in [4]). The difference between species in those genes regulated by NMD is thought to be the cause of the differing phenotypes of animals in which Upf1 has been removed [16,19,22]. Amongst these, Mus musculus lacking Upf1 are embryonic lethal [23], indicating that Upf1, and presumably NMD, plays an important role in mammalian physiology and development. "
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    ABSTRACT: In addition to acting as an RNA quality control pathway, nonsense-mediated mRNA decay (NMD) plays roles in regulating normal gene expression. In particular, the extent to which alternative splicing is coupled to NMD and the roles of NMD in regulating uORF containing transcripts have been a matter of debate. In order to achieve a greater understanding of NMD regulated gene expression we used 2D-DiGE proteomics technology to examine the changes in protein expression induced in HeLa cells by UPF1 knockdown. QPCR based validation of the corresponding mRNAs, in response to both UPF1 knockdown and cycloheximide treatment, identified 17 bona fide NMD targets. Most of these were associated with bioinformatically predicted NMD activating features, predominantly upstream open reading frames (uORFs). Strikingly, however, the majority of transcripts up-regulated by UPF1 knockdown were either insensitive to, or even down-regulated by, cycloheximide treatment. Furthermore, the mRNA abundance of several down-regulated proteins failed to change upon UPF1 knockdown, indicating that UPF1's role in regulating mRNA and protein abundance is more complex than previously appreciated. Among the bona fide NMD targets, we identified a highly conserved AS-NMD event within the 3' UTR of the HNRNPA2B1 gene. Overexpression of GFP tagged hnRNP A2 resulted in a decrease in endogenous hnRNP A2 and B1 mRNA with a concurrent increase in the NMD sensitive isoforms. Despite the large number of changes in protein expression upon UPF1 knockdown, a relatively small fraction of them can be directly attributed to the action of NMD on the corresponding mRNA. From amongst these we have identified a conserved AS-NMD event within HNRNPA2B1 that appears to mediate autoregulation of HNRNPA2B1 expression levels.
    Full-text · Article · Oct 2010 · BMC Genomics
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    • "Instances of transcripts susceptible to NMD can be seen even with annotated protein isoforms – the corresponding values in the case of annotated protein isoforms are 7.9% – suggesting that the observed orphan isoforms are particularly not artifacts due to lack in validating transcript data for NMD. It is appropriate to recollect from literature that NMD machinery rarely down regulates the expression of a transcript completely; 10–30% of transcripts containing premature stop codons survive (NMD-escape) and may lead to production of physiologically relevant levels of truncated protein products [47,48]. "
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