Stress puts TIA on TOP: Figure 1.

Ivanov, Pavel; Kedersha, Nancy; Anderson, Paul

doi:10.1101/gad.17838411

Cited by 43 publications

(33 citation statements)

References 46 publications

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“…strongly suppressed by NMD. Most snoRNA host genes are so-called 59-TOP (terminal oligopyrimidine) genes (Dieci et al 2009), which means that the encoded spliced RNAs contain an oligopyrimidine stretch at the 59 end, ensuring that they are removed from the translationally active pool of cytoplasmic RNA during certain types of stress conditions (Ivanov et al 2011). While this could be a means to up-regulate cytoplasmic levels of ncRNAs under specific conditions, it could also be a way for the cell to save energy, as ribosomes are immediately relieved of a heavy duty of both protein production and RNA degradation.…”

Section: Translate To Degradementioning

confidence: 99%

Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes

et al. 2014

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Eukaryotic RNAs with premature termination codons (PTCs) are eliminated by nonsense-mediated decay (NMD). While human nonsense RNA degradation can be initiated either by an endonucleolytic cleavage event near the PTC or through decapping, the individual contribution of these activities on endogenous substrates has remained unresolved. Here we used concurrent transcriptome-wide identification of NMD substrates and their 59-39 decay intermediates to establish that SMG6-catalyzed endonucleolysis widely initiates the degradation of human nonsense RNAs, whereas decapping is used to a lesser extent. We also show that a large proportion of genes hosting snoRNAs in their introns produce considerable amounts of NMD-sensitive splice variants, indicating that these RNAs are merely by-products of a primary snoRNA production process. Additionally, transcripts from genes encoding multiple snoRNAs often yield alternative transcript isoforms that allow for differential expression of individual coencoded snoRNAs. Based on our findings, we hypothesize that snoRNA host genes need to be highly transcribed to accommodate high levels of snoRNA production and that the expression of individual snoRNAs and their cognate spliced RNA can be uncoupled via alternative splicing and NMD.[Keywords: RNA decapping; endonucleolytic RNA cleavage; intron-encoded snoRNA; nonsense-mediated decay; regulation of snoRNA expression; snoRNA host genes] Supplemental material is available for this article.Received June 2, 2014; revised version accepted October 3, 2014.All functional transcripts, whether they are proteincoding (mRNA) or noncoding (ncRNA), are produced as precursor molecules that undergo various processing steps before they take on their final forms. Eukaryotic RNA polymerase II transcribed genes often encode more than one mature RNA species, as exemplified by the alternative splicing of exonic sequences into a variety of transcript isoforms (Braunschweig et al. 2013;Kornblihtt et al. 2013), usage of alternative promoters (Carninci et al. 2006), and the hosting of smaller RNAs, like miRNAs and snoRNAs, within introns (Brown et al. 2008). Regulation of such alternative RNA production confers great plasticity to eukaryotic gene expression because parameters such as expression specificity, stability, localization, and protein-coding potential can be altered between transcript isoforms (McGlincy and Smith 2008;Valen et al. 2009;Kelemen et al. 2013). However, many alternative processing options also increase the likelihood of mistakes, and, throughout the life span of a transcript, its integrity and functionality is continuously being monitored, which ensures that nonfunctional processing byproducts and erroneously processed or outworn molecules are degraded by decay machineries residing in either the nucleus or the cytoplasm (Doma and Parker 2007;Muhlemann and Jensen 2012;Arraiano et al. 2013). For cytoplasmic RNAs with mRNA-like characteristics, the distinction between functional and nonfunctional is carried out by means of translation-dependent...

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Section: Translate To Degradementioning

confidence: 99%

Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes

et al. 2014

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“…These are based on RNA-binding proteins in combination with micro-RNAs binding mainly to UTRs thereby regulating the initiation step. As examples, selective regulations serve diminished translation of mRNAs with 5Ј terminal oligopyrimidine tracts (44), the usage of iron responsive elements (45), and more recently described the function of cytosolic metadherin as a regulatory RNA-binding protein (46). Especially the regulation by metadherin might be interesting for our observation as it is highly expressed in solid tumors and even further up-regulated by hypoxia (47).…”

Section: Discussionmentioning

confidence: 86%

Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression

Tholen

Wolanski

Stolze

et al. 2015

Journal of Biological Chemistry

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Background: Translational regulation might underlie the high expression levels of the protease cathepsin L (CTSL) associated with poor breast cancer prognosis. Results: Translation of CTSL mRNA is highly stress-resistant and promotes metastasis of murine breast cancer. Conclusion: CTSL mRNA circumvents translational shutdown in cancer-associated stress conditions. Significance: High expression of a metastasis promoting protease is maintained by translational regulation.

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“…Both TIA-1 and AUF-1 were identified as proteins that specifically associate with TOP mRNAs during amino acid starvation. TIA-1 binding to the TOP sequence represses their translation and decreases their association to polysome (Damgaard and Lykke-Andersen 2011;Ivanov et al 2011). While we did not identify these proteins in our screen, we expect them to behave like the 4E-BPs and be specifically recruited to the mRNA 59 cap in conditions where mTOR is inhibited.…”

Section: Discussionmentioning

confidence: 99%

Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5′TOP mRNA translation

et al. 2014

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The mammalian target of rapamycin (mTOR) promotes cell growth and proliferation by promoting mRNA translation and increasing the protein synthetic capacity of the cell. Although mTOR globally promotes translation by regulating the mRNA 59 cap-binding protein eIF4E (eukaryotic initiation factor 4E), it also preferentially regulates the translation of certain classes of mRNA via unclear mechanisms. To help fill this gap in knowledge, we performed a quantitative proteomic screen to identify proteins that associate with the mRNA 59 cap in an mTOR-dependent manner. Using this approach, we identified many potential regulatory factors, including the putative RNA-binding protein LARP1 (La-related protein 1). Our results indicate that LARP1 associates with actively translating ribosomes via PABP and that LARP1 stimulates the translation of mRNAs containing a 59 terminal oligopyrimidine (TOP) motif, encoding for components of the translational machinery. We found that LARP1 associates with the mTOR complex 1 (mTORC1) and is required for global protein synthesis as well as cell growth and proliferation. Together, these data reveal important molecular mechanisms involved in TOP mRNA translation and implicate LARP1 as an important regulator of cell growth and proliferation.

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Stress puts TIA on TOP: Figure 1.

Cited by 43 publications

References 46 publications

Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes

Human nonsense-mediated RNA decay initiates widely by endonucleolysis and targets snoRNA host genes

Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression

Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5′TOP mRNA translation

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