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  • 1.
    Balagopal, Vidya
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Fluch, Lydia
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nissan, Tracy
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ways and means of eukaryotic mRNA decay2012In: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, ISSN 1874-9399, Vol. 1819, no 6, p. 593-603Article, review/survey (Refereed)
    Abstract [en]

    Messenger RNA degradation is an important point of control for gene expression. Genome-wide studies on mRNA stability have demonstrated its importance in adaptation and stress response. Most of the key players in mRNA decay appear to have been identified. The study of these proteins brings insight into the mechanism of general and specific targeting of transcripts for degradation. Recruitment and assembly of mRNP complexes enhance and bring specificity to mRNA decay. mRNP complexes can form larger structures that have been found to be ubiquitous in nature. Discovery of P-Bodies, an archetype of this sort of aggregates, has generated interest in the question of where mRNA degrades. This is currently an open question under extensive investigation. This review will discuss in detail the recent developments in the regulation of mRNA decay focusing on yeast as a model system. 

  • 2. Buchan, J Ross
    et al.
    Nissan, Tracy
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Parker, Roy
    Analyzing p-bodies and stress granules in Saccharomyces cerevisae2010In: Guide to yeast genetics: functional genomics, proteomics, and other systems analysis / [ed] Jonathan Weissman, Christine Guthrie, Gerald R. Fink, San Diego: Academic Press, 2010, 2, Vol. 470, p. 619-640Chapter in book (Refereed)
    Abstract [en]

    Eukaryotic cells contain at least two types of cytoplasmic RNA protein (RNP) granules that contain nontranslating mRNAs. One such RNP granule is a P-body, which contains translationally inactive mRNAs and proteins involved in mRNA degradation and translation repression. A second such RNP granule is a stress granule which also contains mRNAs, some RNA binding proteins and several translation initiation factors, suggesting these granules contain mRNAs stalled in translation initiation. In this chapter, we describe methods to analyze P-bodies and stress granules in Saccharomyces cerevisiae, including procedures to determine if a protein or mRNA can accumulate in either granule, if an environmental perturbation or mutation affects granule size and number, and granule quantification methods.

  • 3.
    Huch, Susanne
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gommlich, Jessie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Muppavarapu, Mridula
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Beckham, Carla
    Nissan, Tracy
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Membrane-association of mRNA decapping factors is independent of stress in budding yeast2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 25477Article in journal (Refereed)
    Abstract [en]

    Recent evidence has suggested that the degradation of mRNA occurs on translating ribosomes or alternatively within RNA granules called P bodies, which are aggregates whose core constituents are mRNA decay proteins and RNA. In this study, we examined the mRNA decapping proteins, Dcp1, Dcp2, and Dhh1, using subcellular fractionation. We found that decapping factors co-sediment in the polysome fraction of a sucrose gradient and do not alter their behaviour with stress, inhibition of translation or inhibition of the P body formation. Importantly, their localisation to the polysome fraction is independent of the RNA, suggesting that these factors may be constitutively localised to the polysome. Conversely, polysomal and post-polysomal sedimentation of the decapping proteins was abolished with the addition of a detergent, which shifts the factors to the non-translating RNP fraction and is consistent with membrane association. Using a membrane otation assay, we observed the mRNA decapping factors in the lower density fractions at the buoyant density of membrane-associated proteins. These observations provide further evidence that mRNA decapping factors interact with subcellular membranes, and we suggest a model in which the mRNA decapping factors interact with membranes to facilitate regulation of mRNA degradation. 

  • 4.
    Huch, Susanne
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Müller, Maren
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Muppavarapu, Mridula
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gommlich, Jessie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Balagopal, Vidya
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nissan, Tracy
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The decapping activator Edc3 and the Q/N-rich domain of Lsm4 function together to enhance mRNA stability and alter mRNA decay pathway dependence in Saccharomyces cerevisiae2016In: Biology Open, ISSN 2046-6390, Vol. 5, no 10, p. 1388-1399Article in journal (Refereed)
    Abstract [en]

    The rate and regulation of mRNA decay are major elements in the proper control of gene expression. Edc3 and Lsm4 are two decapping activator proteins that have previously been shown to function in the assembly of RNA granules termed P bodies. Here, we show that deletion of edc3, when combined with a removal of the glutamine/asparagine rich region of Lsm4 (edc3Δ lsm4ΔC) reduces mRNA stability and alters pathways of mRNA degradation. Multiple tested mRNAs exhibited reduced stability in the edc3Δ lsm4ΔC mutant. The destabilization was linked to an increased dependence on Ccr4-mediated deadenylation and mRNA decapping. Unlike characterized mutations in decapping factors that either are neutral or are able to stabilize mRNA, the combined edc3Δ lsm4ΔC mutant reduced mRNA stability. We characterized the growth and activity of the major mRNA decay systems and translation in double mutant and wild-type yeast. In the edc3Δ lsm4ΔC mutant, we observed alterations in the levels of specific mRNA decay factors as well as nuclear accumulation of the catalytic subunit of the decapping enzyme Dcp2. Hence, we suggest that the effects on mRNA stability in the edc3Δ lsm4ΔC mutant may originate from mRNA decay protein abundance or changes in mRNPs or alternatively may imply a role for P bodies in mRNA stabilization.

  • 5.
    Huch, Susanne
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nissan, Tracy
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    An mRNA decapping mutant deficient in P body assembly limits mRNA stabilization in response to osmotic stress2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 44395Article in journal (Refereed)
    Abstract [en]

    Yeast is exposed to changing environmental conditions and must adapt its genetic program to provide a homeostatic intracellular environment. An important stress for yeast in the wild is high osmolarity. A key response to this stress is increased mRNA stability primarily by the inhibition of deadenylation. We previously demonstrated that mutations in decapping activators (edc3∆ lsm4∆C), which result in defects in P body assembly, can destabilize mRNA under unstressed conditions. We wished to examine whether mRNA would be destabilized in the edc3∆ lsm4∆C mutant as compared to the wild-type in response to osmotic stress, when P bodies are intense and numerous. Our results show that the edc3∆ lsm4∆C mutant limits the mRNA stability in response to osmotic stress, while the magnitude of stabilization was similar as compared to the wild-type. The reduced mRNA stability in the edc3∆ lsm4∆C mutant was correlated with a shorter PGK1 poly(A) tail. Similarly, the MFA2 mRNA was more rapidly deadenylated as well as significantly stabilized in the ccr4∆ deadenylation mutant in the edc3∆ lsm4∆C background. These results suggest a role for these decapping factors in stabilizing mRNA and may implicate P bodies as sites of reduced mRNA degradation.

  • 6.
    Huch, Susanne
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nissan, Tracy
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Interrelations between translation and general mRNA degradation in yeast2014In: Wiley Interdisciplinary Reviews: RNA, ISSN 1757-7012, Vol. 5, no 6, p. 747-763Article, review/survey (Refereed)
    Abstract [en]

    Messenger RNA (mRNA) degradation is an important element of gene expression that can be modulated by alterations in translation, such as reductions in initiation or elongation rates. Reducing translation initiation strongly affects mRNA degradation by driving mRNA toward the assembly of a decapping complex, leading to decapping. While mRNA stability decreases as a consequence of translational inhibition, in apparent contradiction several external stresses both inhibit translation initiation and stabilize mRNA. A key difference in these processes is that stresses induce multiple responses, one of which stabilizes mRNAs at the initial and rate-limiting step of general mRNA decay. Because this increase in mRNA stability is directly induced by stress, it is independent of the translational effects of stress, which provide the cell with an opportunity to assess its response to changing environmental conditions. After assessment, the cell can store mRNAs, reinitiate their translation or, alternatively, embark on a program of enhanced mRNA decay en masse. Finally, recent results suggest that mRNA decay is not limited to non-translating messages and can occur when ribosomes are not initiating but are still elongating on mRNA. This review will discuss the models for the mechanisms of these processes and recent developments in understanding the relationship between translation and general mRNA degradation, with a focus on yeast as a model system.

  • 7.
    Muppavarapu, Mridula
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Huch, Susanne
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nissan, Tracy
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The cytoplasmic mRNA degradation factor Pat1 is required for rRNA processing2016In: RNA Biology, ISSN 1547-6286, Vol. 13, no 4, p. 455-465Article in journal (Refereed)
    Abstract [en]

    Pat1 is a key cytoplasmic mRNA degradation factor, the loss of which severely increases mRNA half-lives. Several recent studies have shown that Pat1 can enter the nucleus and can shuttle between the nucleus and the cytoplasm. As a result, many nuclear roles have been proposed for Pat1. In this study, we analyzed four previously suggested nuclear roles of Pat1 and show that Pat1 is not required for efficient pre-mRNA splicing or pre-mRNA decay in yeast. However, lack of Pat1 results in accumulation of pre-rRNA processing intermediates. Intriguingly, we identified a novel genetic relationship between Pat1 and the rRNA decay machinery, specifically the exosome and the TRAMP complex. While the pre-rRNA processing intermediates that accumulate in the pat1 deletion mutant are, at least to some extent, recognized as aberrant by the rRNA degradation machinery, it is unlikely that these accumulations are the cause of their synthetic sick relationship. Here, we show that the dysregulation of the levels of mRNAs related to ribosome biogenesis could be the cause of the accumulation of the pre-rRNA processing intermediates.Although our results support a role for Pat1 in transcription, they nevertheless suggest that the primary cause of the dysregulated mRNA levels is most likely due to Pat1’s role in mRNA decapping and mRNA degradation.

  • 8.
    Nissan, Tracy A
    et al.
    Biochemie-Zentrum Heidelberg, Universität Heidelberg, Germany.
    Bassler, Jochen
    Petfalski, Elisabeth
    Tollervey, David
    Hurt, Ed
    60S pre-ribosome formation viewed from assembly in the nucleolus until export to the cytoplasm2002In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 21, no 20, p. 5539-5547Article in journal (Refereed)
    Abstract [en]

    60S ribosomes undergo initial assembly in the nucleolus before export to the cytoplasm and recent analyses have identified several nucleolar pre-60S particles. To unravel the steps in the pathway of ribosome formation, we have purified the pre-60S ribosomes associated with proteins predicted to act at different stages as the pre-ribosomes transit from the nucleolus through the nucleoplasm and are then exported to the cytoplasm for final maturation. About 50 non-ribosomal proteins are associated with the early nucleolar pre-60S ribosomes. During subsequent maturation and transport to the nucleoplasm, many of these factors are removed, while others remain attached and additional factors transiently associate. When the 60S precursor particles are close to exit from the nucleus they associate with at least two export factors, Nmd3 and Mtr2. As the 60S pre-ribosome reaches the cytoplasm, almost all of the factors are dissociated. These data provide an initial biochemical map of 60S ribosomal subunit formation on its path from the nucleolus to the cytoplasm.

  • 9.
    Nissan, Tracy A
    et al.
    Biochemie-Zentrum der Universität Heidelberg.
    Galani, Kyriaki
    Maco, Bohumil
    Tollervey, David
    Aebi, Ueli
    Hurt, Ed
    A pre-ribosome with a tadpole-like structure functions in ATP-dependent maturation of 60S subunits2004In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 15, no 2, p. 295-301Article in journal (Refereed)
    Abstract [en]

    Analyses of isolated pre-ribosomes yielded biochemical "snapshots" of the dynamic, nascent 60S and 40S subunits during their path from the nucleolus to the cytoplasm. Here, we present the structure of a pre-60S ribosomal intermediate located in the nucleoplasm. A huge dynein-related AAA-type ATPase (Rea1) and the Rix1 complex (Rix1-Ipi1-Ipi3) are components of an extended (approximately 45 nm long) pre-60S particle. Antibody crosslinking in combination with electron microscopy revealed that the Rea1 localizes to the "tail" region and ribosomal proteins to the "head" region of the elongated "tadpole-like" structure. Furthermore, in vitro treatment with ATP induces dissociation of Rea1 from the pre-60S subunits. Rea1 and the Rix1 complex could mediate ATP-dependent remodeling of 60S subunits and subsequent export from the nucleoplasm to the cytoplasm.

  • 10.
    Nissan, Tracy
    et al.
    The University of Arizona, Department of Molecular and Cellular Biology and Howard Hughes Medical Institute, Tucson, Arizona, USA.
    Parker, Roy
    Analyzing P-bodies in Saccharomyces cerevisiae2008In: Methods in Enzymology, ISSN 0076-6879, E-ISSN 1557-7988, ISSN 1557-7988, Vol. 448, p. 507-520Article in journal (Refereed)
    Abstract [en]

    Cytoplasmic processing bodies, or P-bodies, are RNA-protein granules found in eukaryotic cells. P-bodies contain non-translating mRNAs and proteins involved in mRNA degradation and translational repression. P-bodies, and the mRNPs within them, have been implicated in mRNA storage, mRNA degradation, and translational repression. The analysis of mRNA turnover often involves the analysis of P-bodies. In this chapter, we describe methods to analyze P-bodies in the budding yeast, Saccharomyces cerevisiae, including procedures to determine whether a protein or mRNA can accumulate in P-bodies, whether an environmental perturbation or mutation affects P-body size and number, and methods to quantify P-bodies.

  • 11.
    Nissan, Tracy
    et al.
    University of Arizona, Tucson, Arizona, USA.
    Parker, Roy
    Computational analysis of miRNA-mediated repression of translation: implications for models of translation initiation inhibition2008In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 14, no 8, p. 1480-1491Article in journal (Refereed)
    Abstract [en]

    The mechanism by which miRNAs inhibit translation has been under scrutiny both in vivo and in vitro. Divergent results have led to the suggestion that miRNAs repress translation by a variety of mechanisms including blocking the function of the cap in stimulating translation. However, these analyses largely only examine the final output of the multistep process of translation. This raises the possibility that when different steps in translation are rate limiting, miRNAs might show different effects on protein production. To examine this possibility, we modeled the process of translation initiation and examined how the effects of miRNAs under different conditions might be explained. Our results suggest that different effects of miRNAs on protein production in separate experiments could be due to differences in rate-limiting steps. This analysis does not rule out that miRNAs directly repress the function of the cap structure, but it demonstrates that the observations used to argue for this effect are open to alternative interpretations. Taking all the data together, our analysis is consistent with the model that miRNAs may primarily repress translation initiation at a late step.

  • 12.
    Nissan, Tracy
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Rajyaguru, Purusharth
    She, Meipei
    Song, Haiwei
    Parker, Roy
    Decapping activators in Saccharomyces cerevisiae act by multiple mechanisms2010In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 39, no 5, p. 773-783Article in journal (Refereed)
    Abstract [en]

    Eukaryotic mRNA degradation often occurs in a process whereby translation initiation is inhibited and the mRNA is targeted for decapping. In yeast cells, Pat1, Scd6, Edc3, and Dhh1 all function to promote decapping by an unknown mechanism(s). We demonstrate that purified Scd6 and a region of Pat1 directly repress translation in vitro by limiting the formation of a stable 48S preinitiation complex. Moreover, while Pat1, Edc3, Dhh1, and Scd6 all bind the decapping enzyme, only Pat1 and Edc3 enhance its activity. We also identify numerous direct interactions between Pat1, Dcp1, Dcp2, Dhh1, Scd6, Edc3, Xrn1, and the Lsm1-7 complex. These observations identify three classes of decapping activators that function to directly repress translation initiation and/or stimulate Dcp1/2. Moreover, Pat1 is identified as critical in mRNA decay by first inhibiting translation initiation, then serving as a scaffold to recruit components of the decapping complex, and finally activating Dcp2.

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