Targeting of Aberrant mRNAs to Cytoplasmic Processing Bodies

Department of Molecular and Cellular Biology, University of Arizona, Tucson, 85721, USA.
Cell (Impact Factor: 32.24). 07/2006; 125(6):1095-109. DOI: 10.1016/j.cell.2006.04.037
Source: PubMed


In eukaryotes, a specialized pathway of mRNA degradation termed nonsense-mediated decay (NMD) functions in mRNA quality control by recognizing and degrading mRNAs with aberrant termination codons. We demonstrate that NMD in yeast targets premature termination codon (PTC)-containing mRNA to P-bodies. Upf1p is sufficient for targeting mRNAs to P-bodies, whereas Upf2p and Upf3p act, at least in part, downstream of P-body targeting to trigger decapping. The ATPase activity of Upf1p is required for NMD after the targeting of mRNAs to P-bodies. Moreover, Upf1p can target normal mRNAs to P-bodies but not promote their degradation. These observations lead us to propose a new model for NMD wherein two successive steps are used to distinguish normal and aberrant mRNAs.

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    • "Many proteins that are involved in mRNA decay, such as CCR4-NOT deadenylase components, DCP2, PATL1, EDC3, DDX6, and LSM14, are enriched in dynamic cytoplasmic foci called processing bodies (P-bodies) (Kedersha and Anderson, 2009; Sheth and Parker, 2006). A key protein that promotes P-body formation is the eIF4E-transporter protein, 4E-T (Ferraiuolo et al., 2005). "
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    ABSTRACT: Eukaryotic mRNA degradation often initiates with the recruitment of the CCR4-NOT deadenylase complex and decay factors to the mRNA 3' terminus. How the 3'-proximal decay machinery interacts with the 5'-terminal cap structure in order to engender mRNA decapping and 5'-3' degradation is unclear. Human 4E-T is an eIF4E-binding protein that has been reported to promote mRNA decay, albeit via an unknown mechanism. Here, we show that 4E-T is a component of the mRNA decay machinery and interacts with factors including DDX6, LSM14, and the LSM1-7-PAT1 complex. We also provide evidence that 4E-T associates with, and enhances the decay of, mRNAs targeted by the CCR4-NOT deadenylase complex, including microRNA targets. Importantly, we demonstrate that 4E-T must interact with eIF4E to engender mRNA decay. Taken together, our data support a model where 4E-T promotes mRNA turnover by physically linking the 3'-terminal mRNA decay machinery to the 5' cap via its interaction with eIF4E. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 05/2015; 11(9). DOI:10.1016/j.celrep.2015.04.065 · 8.36 Impact Factor
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    • "The up-frameshift proteins UPF1, UPF2, and UPF3 are essential factors of NMD. In yeast, UPF1-3 are involved in recognition and targeting PTC-containing mRNA to PB (Sheth and Parker, 2006; Nyikó et al., 2009). UPF1-3 are cytoplasmic, but they co-localize to DCP2 in the dcp1Δ strain, theoretically by accumulation of non-degraded aberrant mRNAs or other substrates of NMD. "
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    ABSTRACT: mRNA accumulation is tightly regulated by diverse molecular pathways. The identification and characterization of enzymes and regulatory proteins involved in controlling the fate of mRNA offers the possibility to broaden our understanding of posttranscriptional gene regulation. Processing bodies (P bodies, PB) are cytoplasmic protein complexes involved in degradation and translational arrest of mRNA. Composition and dynamics of these subcellular structures have been studied in animal systems, yeasts and in the model plant Arabidopsis. Their assembly implies the aggregation of specific factors related to decapping, deadenylation, and exoribonucleases that operate synchronously to regulate certain mRNA targets during development and adaptation to stress. Although the general function of PB along with the flow of genetic information is understood, several questions still remain open. This review summarizes data on the composition, potential molecular roles, and biological significance of PB and potentially related proteins in Arabidopsis.
    Frontiers in Plant Science 05/2014; 5:201. DOI:10.3389/fpls.2014.00201 · 3.95 Impact Factor
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    • "This allows the visualization of the mRNA via coexpression of the MS2 coat protein fused to three green fluorescent proteins (CP–GFP 3 ). Such systems have been used extensively to examine the localization of mRNAs in a wide range of biological systems (Haim et al., 2007; Hamada et al., 2003; Sheth and Parker, 2006). Key advantages of this yeast system are that the control elements associated with mRNA transcription and processing [promoters, UTRs, poly(A) sites and terminators] remain intact, as the MS2-binding sites are inserted directly and precisely into the 39UTR of the endogenous gene at its chromosomal locus (Haim et al., 2007). "
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    ABSTRACT: The relocalization of translationally repressed mRNAs to mRNA Processing bodies (P-bodies) is a key consequence of cellular stress across many systems. P-bodies harbor mRNA degradation components and are implicated in mRNA decay, but the relative timing and control of mRNA relocalization to P-bodies is poorly understood. We used the MS2-GFP system to follow the movement of specific endogenous mRNAs in live yeast cells after nutritional stress. It appears that the relocalization of mRNA to P-bodies after stress is bi-phasic: some mRNAs are present early, whereas others are recruited much later concomitant with recruitment of translation initiation factors, such as eIF4E. We also find that Bfr1p is a late phase localizing P-body protein that is important for the delayed entry of the specific tested mRNAs to P-bodies. Therefore, for the mRNAs tested, relocalization to P-bodies varies both in terms of the kinetics and factor requirements. This work highlights a potential new regulatory juncture in gene expression that would facilitate the overall rationalization of protein content required for adaptation to stress.
    Journal of Cell Science 01/2014; 127(6). DOI:10.1242/jcs.139055 · 5.43 Impact Factor
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