| 1. |
- Alao, John Patrick, 1973, et al.
(author)
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Inhibition of type I histone deacetylase increases resistance of checkpoint-deficient cells to genotoxic agents through mitotic delay
- 2009
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In: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 8, s. 2606-2615
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Journal article (peer-reviewed)abstract
- Histone deacetylase (HDAC) inhibitors potently inhibit tumor growth and are currently being evaluated for their efficacy as chemosensitizers and radiosensitizers. This efficacy is likely to be limited by the fact that HDACinhibitors also induce cell cycle arrest. Deletion of the class I HDACRpd3 has been shown to specifically suppress the sensitivity of Saccharomyces cerevisiae DNA damage checkpoint mutants to UV and hydroxyurea. We show that in the fission yeast Schizosaccharomyces pombe, inhibition of the homologous class I HDACspe cifically suppresses the DNA damage sensitivity of checkpoint mutants. Importantly, the prototype HDACinhibitor Trichostatin A also suppressed the sensitivity of DNA damage checkpoint but not of DNA repair mutants to UV and HU. TSA suppressed DNA damage activity independently of the mitogen-activated protein kinase–dependent and spindle checkpoint pathways. We show that TSA delays progression into mitosis and propose that this is the main mechanism for suppression of the DNA damage sensitivity of S. pombe checkpoint mutants, partially compensating for the loss of the G2 checkpoint pathway. Our studies also show that the ability of HDACinhibitors to suppress DNA damage sensitivity is not species specific. Class I HDACs are the major target of HDAC inhibitors and cancer cells are often defective in checkpoint activation. Effective use of these agents as chemosensitizers and radiosensitizers may require specific treatment schedules that circumvent their inhibition of cell cycle progression.
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| 2. |
- Alao, John Patrick, 1973, et al.
(author)
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Rad3 and Sty1 function in S. pombe: an integrated response to DNA damage and environmental stress?
- 2008
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In: Molecular Microbiology. - : Wiley. - 0950-382X. ; 68, s. 246-254
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Research review (peer-reviewed)abstract
- In Schizosaccharomyces pombe, the Ataxia Telangiectasia-mutated (Atm)/Atm and Rad 3 Related (Atr) homologue Rad3 is an essential regulator of the response to DNA damage and stalled replication forks. Rad3 activates the downstream kinases Chk1 and Cds1. These kinases in turn inhibit cell cycle progression by mediating Cdc2 phosphorylation. Studies in both yeast and mammalian cells suggest additional roles for Rad3 in regulating cellular responses to environmental stress. In S. pombe, cellular responses to various environmental stresses are regulated primarily through the stress-activated MAP kinase p38 homologue Sty1. An important function of Sty1 is to drive cells rapidly through mitosis by facilitating the accumulation of Cdc25. Interestingly, Sty1 is activated simultaneously with Rad3 following exposure to UV radiation or ionizing radiation (IR). Similarly, exposure to environmental stresses induces the expression of rad3+, cds1+ and other checkpoint regulator genes. It is currently unclear how the pathways regulated by Sty1 and Rad3 and their opposing effects on mitosis are integrated. Recent studies suggest that Sty1 and Rad3 function together to regulate the expression of several stress response genes following exposure to IR. In this review, we discuss current knowledge on the interaction of Rad3/Atm and Sty1/p38 in regulating cellular responses to environmental stress and DNA damage.
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| 3. |
- Alao, John Patrick, 1973, et al.
(author)
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The ATM and ATR inhibitors CGK733 and caffeine suppress cyclin D1 levels and inhibit cell proliferation
- 2009
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In: Radiation Oncology. ; 4
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Journal article (peer-reviewed)abstract
- The ataxia telangiectasia mutated (ATM) and the ATM- related (ATR) kinases play a central role in facilitating the resistance of cancer cells to genotoxic treatment regimens. The components of the ATM and ATR regulated signaling pathways thus provide attractive pharmacological targets, since their inhibition enhances cellular sensitivity to chemo- and radiotherapy. Caffeine as well as more specific inhibitors of ATM (KU55933) or ATM and ATR (CGK733) have recently been shown to induce cell death in drug-induced senescent tumor cells. Addition of these agents to cancer cells previously rendered senescent by exposure to genotoxins suppressed the ATM mediated p21 expression required for the survival of these cells. The precise molecular pharmacology of these agents however, is not well characterized. Herein, we report that caffeine, CGK733, and to a lesser extent KU55933, inhibit the proliferation of otherwise untreated human cancer and non-transformed mouse fibroblast cell lines. Exposure of human cancer cell lines to caffeine and CGK733 was associated with a rapid decline in cyclin D1 protein levels and a reduction in the levels of both phosphorylated and total retinoblastoma protein (RB). Our studies suggest that observations based on the effects of these compounds on cell proliferation and survival must be interpreted with caution. The differential effects of caffeine/ CGK733 and KU55933 on cyclin D1 protein levels suggest that these agents will exhibit dissimilar molecular pharmacological profiles.
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| 4. |
- Asp, Eva, 1970, et al.
(author)
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Fission yeast mitogen-activated protein kinase Sty1 interacts with translation factors
- 2008
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In: Eukaryot. Cell. ; 7, s. 328-338
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Journal article (peer-reviewed)abstract
- Signaling by stress-activated mitogen-activated protein kinase (MAPK) pathways influences translation efficiency in mammalian cells and budding yeast. We have investigated the stress-activated MAPK from fission yeast, Sty1, and its downstream protein kinase, Mkp1/Srk1, for physically associated proteins using tandem affinity purification tagging. We find Sty1, but not Mkp1, to bind to the translation elongation factor eukaryotic elongation factor 2 (eEF2) and the translation initiation factor eukaryotic initiation factor 3a (eIF3a). The Sty1-eIF3a interaction is weakened under oxidative or hyperosmotic stress, whereas the Sty1-eEF2 interaction is stable. Nitrogen deprivation causes a transient strengthening of both the Sty1-eEF2 and the Sty1-Mkp1 interactions, overlapping with the time of maximal Sty1 activation. Analysis of polysome profiles from cells under oxidative stress, or after hyperosmotic shock or nitrogen deprivation, shows that translation in sty1 mutant cells recovers considerably less efficiently than that in the wild type. Cells lacking the Sty1-regulated transcription factor Atf1 are deficient in maintaining and recovering translational activity after hyperosmotic shock but not during oxidative stress or nitrogen starvation. In cells lacking Sty1, eIF3a levels are decreased, and phosphorylation of eIF3a is reduced. Taken together, our data point to a central role in translational adaptation for the stress-activated MAPK pathway in fission yeast similar to that in other investigated eukaryotes, with the exception that fission yeast MAPK-activated protein kinases seem not to be directly involved in this process.
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| 5. |
- Axelson-Fisk, Marina, et al.
(author)
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Comparative genomics and gene finding in fungi
- 2006
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In: Topics in Current Genetics. ; 15, s. 1-28
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Research review (peer-reviewed)abstract
- In the spring of 2005, we had access to 18 fully sequenced fungal genomes, and more are coming rapidly. New approaches and methods are being developed to harvest this information source to derive functional predictions and understanding of genome anatomy. Comparative genomics also tells us stories about the evolution of yeasts and filamentous fungi, and the genome rearrangements that marked their history. For example, several genes encoding proteins required for heterochromatin formation and RNA interference have been lost uniformly throughout the Hemiascomycetes, although some genes remain in a few species in a scattered pattern. Being the first eukaryote to have its genome fully sequenced, Saccharomyces cerevisiae was the forerunner for in silico methods of genome annotation in general, and gene finding in particular. Lessons learned from the comparatively simple genome of this budding yeast have paved the way for efficient genome analysis in other fungi as well as eukaryotes in general. Several fungal species are of important applied interest for mankind, and so it is essential to utilise comparative genomics to derive functional information about them. The set of fungal genomes: simple, related in evolution, and with a high density of functional information, can serve as a highly efficient test bed for the further development of comparative genomics.
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| 6. |
- Axelson-Fisk, Marina, 1972, et al.
(author)
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Gene finding in fungal genomes
- 2005
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In: Topics in Current Genetics: Comparative genomics using fungi as models. - 9783540314806 ; , s. 1-28
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Book chapter (other academic/artistic)
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| 7. |
- Barreto, L., et al.
(author)
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A peroxisomal glutathione transferase of Saccharomyces cerevisiae is functionally related to sulfur amino acid metabolism
- 2006
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In: Eukaryot Cell. ; 5:10, s. 1748-59
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Journal article (peer-reviewed)abstract
- Saccharomyces cerevisiae cells contain three omega-class glutathione transferases with glutaredoxin activity (Gto1, Gto2, and Gto3), in addition to two glutathione transferases (Gtt1 and Gtt2) not classifiable into standard classes. Gto1 is located at the peroxisomes, where it is targeted through a PTS1-type sequence, whereas Gto2 and Gto3 are in the cytosol. Among the GTO genes, GTO2 shows the strongest induction of expression by agents such as diamide, 1-chloro-2,4-dinitrobenzene, tert-butyl hydroperoxide or cadmium, in a manner that is dependent on transcriptional factors Yap1 and/or Msn2/4. Diamide and 1-chloro-2,4-dinitrobenzene (causing depletion of reduced glutathione) also induce expression of GTO1 over basal levels. Phenotypic analyses with single and multiple mutants in the S. cerevisiae glutathione transferase genes show that, in the absence of Gto1 and the two Gtt proteins, cells display increased sensitivity to cadmium. A gto1-null mutant also shows growth defects on oleic acid-based medium, which is indicative of abnormal peroxisomal functions, and altered expression of genes related to sulfur amino acid metabolism. As a consequence, growth of the gto1 mutant is delayed in growth medium without lysine, serine, or threonine, and the mutant cells have low levels of reduced glutathione. The role of Gto1 at the S. cerevisiae peroxisomes could be related to the redox regulation of the Str3 cystathionine beta-lyase protein. This protein is also located at the peroxisomes in S. cerevisiae, where it is involved in transulfuration of cysteine into homocysteine, and requires a conserved cysteine residue for its biological activity.
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| 8. |
- Bilsland, Elizabeth, 1973, et al.
(author)
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The Bre5/Ubp3 ubiquitin protease complex from budding yeast contributes to the cellular response to DNA damage
- 2007
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In: DNA Repair (Amst). - : Elsevier BV. - 1568-7864. ; 6:10, s. 1471-84
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Journal article (peer-reviewed)abstract
- The ubiquitination status of proteins can control numerous aspects of protein function through targeted destruction or by altering protein-protein interactions, subcellular localization, or enzymatic activity. In addition to enzymes that mediate the conjugation of ubiquitin moieties to target proteins, there are enzymes that catalyze the removal of ubiquitin, termed ubiquitin proteases. One such ubiquitin protease, Ubp3, exists in a complex with a partner protein: Bre5. This complex has been implicated in a variety of cellular activities, and was recently identified in large-scale screens for genetic interactions with known components of the DNA damage response pathway. We found that this complex plays a role in the cellular response to the DNA damaging agent phleomycin and strains lacking the complex have a defect in non-homologous end joining. Although this complex is also important for telomeric silencing, maintenance of the cell wall, and global transcriptional regulation, we present evidence suggesting that the role of this complex in DNA damage responses is distinct from these other roles. First, we found that Ubp3/Bre5 functions antagonistically with Bul1 in DNA damage responses, but not in its other cellular functions. Additionally, we have generated mutants of Bre5 that are specifically defective in DNA damage responses.
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| 9. |
- Corbacho, Isaac, et al.
(author)
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Genome-wide expression profile of the mnn2Δ mutant of Saccharomyces cerevisiae
- 2006
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In: Antonie van Leeuwenhoek. - : Springer Science and Business Media LLC. - 0003-6072 .- 1572-9699. ; 89:3-4, s. 485-494
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Journal article (peer-reviewed)abstract
- Abstract The MNN2 gene of S. cerevisiae encodes an α (1,2) mannosyl transferase required for branching the outer chain of N-linked oligosaccharides (Rayner J.C. and Munro S. 1998. J. Biol. Chem. 273: 2683626843) and it also seems to have some effect on the transfer of mannosyl phosphate groups to the inner core (Olivero I. et al. 2000. FEBS Lett. 475: 111116). In order to reveal possible interactions of MNN2 expression with other cellular pathways, we analyzed the transcriptome of the deletion mutant S. cerevisiae mnn2Δ using cDNA microarrays. We found 151 genes that showed an altered expression level of ≥2-fold, 58 of them up-regulated and 93 down-regulated. Quite a high proportion of these genes (29%) encode unclassified proteins. In contrast to other defects affecting the integrity of the cell wall, deletion of MNN2 does not stimulate the expression of any of the genes included in the previously defined cell wall compensatory cluster (Lagorce et al. 2003. J. Biol. Chem. 278: 2034520357). We also found that 15% of the selected genes are related to central metabolic pathways. In addition, the mnn2Δ strain seems to have a certain level of stimulation of DNA processing reactions while some genes involved in intracellular transport pathways are under-regulated
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| 10. |
- Cvijovic, Marija, 1977, et al.
(author)
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Identification of putative regulatory upstream ORFs in the yeast genome using heuristics and evolutionary conservation
- 2007
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In: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 8
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The translational efficiency of an mRNA can be modulated by upstream open reading frames (uORFs) present in certain genes. A uORF can attenuate translation of the main ORF by interfering with translational reinitiation at the main start codon. uORFs also occur by chance in the genome, in which case they do not have a regulatory role. Since the sequence determinants for functional uORFs are not understood, it is difficult to discriminate functional from spurious uORFs by sequence analysis. RESULTS: We have used comparative genomics to identify novel uORFs in yeast with a high likelihood of having a translational regulatory role. We examined uORFs, previously shown to play a role in regulation of translation in Saccharomyces cerevisiae, for evolutionary conservation within seven Saccharomyces species. Inspection of the set of conserved uORFs yielded the following three characteristics useful for discrimination of functional from spurious uORFs: a length between 4 and 6 codons, a distance from the start of the main ORF between 50 and 150 nucleotides, and finally a lack of overlap with, and clear separation from, neighbouring uORFs. These derived rules are inherently associated with uORFs with properties similar to the GCN4 locus, and may not detect most uORFs of other types. uORFs with high scores based on these rules showed a much higher evolutionary conservation than randomly selected uORFs. In a genome-wide scan in S. cerevisiae, we found 34 conserved uORFs from 32 genes that we predict to be functional; subsequent analysis showed the majority of these to be located within transcripts. A total of 252 genes were found containing conserved uORFs with properties indicative of a functional role; all but 7 are novel. Functional content analysis of this set identified an overrepresentation of genes involved in transcriptional control and development. CONCLUSION: Evolutionary conservation of uORFs in yeasts can be traced up to 100 million years of separation. The conserved uORFs have certain characteristics with respect to length, distance from each other and from the main start codon, and folding energy of the sequence. These newly found characteristics can be used to facilitate detection of other conserved uORFs.
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| 11. |
- Hult, Malin, 1974, et al.
(author)
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SAPK and control of translation
- 2008
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In: Topics in Current Genetics. ; 20, s. 299-310
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Research review (peer-reviewed)abstract
- Posttranscriptional control of translation is essential for rapid adaptation to changing environmental conditions, and also in some instances of hormonal control. General translational control, which affects all mRNAs, can target the initiation or the elongation step. General regulation of initiation commonly targets the translation initiation factors eIF2α or eIF4E; a common target for regulation of elongation is eEF-2. In all these cases, SAPK signalling has been shown to play a role. Posttranscriptional regulation of individual mRNAs is ultimately determined by cis-acting sequences, most famously the ARE sequences. SAPK’s are also implicated in translational control of individual mRNA species through ARE’s and probably other sequence elements. In addition, SAPK signalling can influence the use of alternative translation start sites, and transcription and mRNA stability of components of the protein synthesis machinery. While most knowledge of translational control is derived from mammalian systems, yeast genetics is recently providing complementary understanding.
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| 12. |
- Jansson, Kristina, 1969, et al.
(author)
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The tumor suppressor homolog in fission yeast, myh1+, displays a strong interaction with the checkpoint gene rad1
- 2008
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In: Mutation Research. - : Elsevier BV. ; 644, s. 48-55
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Journal article (peer-reviewed)abstract
- The DNA glycosylase MutY is strongly conserved in evolution, and homologs are found in most eukaryotes and prokaryotes examined. This protein is implicated in repair of oxidative DNA damage, in particular adenine mispaired opposite 7,8-dihydro-8-oxoguanine. Previous investigations in Escherichia coli, fission yeast, and mammalian cells show an association of mutations in MutY homologs with a mutator phenotype and carcinogenesis. Eukaryotic MutY homologs physically associate with several proteins with a role in replication, DNA repair, and checkpoint signaling, specifically the trimeric 9-1-1 complex. In a genetic investigation of the fission yeast MutY homolog, myh1+, we show that the myh1 mutation confers a moderately increased UV sensitivity alone and in combination with mutations in several DNA repair genes. The myh1 rad1, and to a lesser degree myh1 rad9, double mutants display a synthetic interaction resulting in enhanced sensitivity to DNA damaging agents and hydroxyurea. UV irradiation of myh1 rad1 double mutants results in severe chromosome segregation defects and visible DNA fragmentation, and a failure to activate the checkpoint. Additionally, myh1 rad1 double mutants exhibit morphological defects in the absence of DNA damaging agents.We also found a moderate suppression of the slow growth and UV sensitivity of rhp51 mutants by the myh1 mutation. Our results implicate fission yeast Myh1 in repair of a wider range of DNA damage than previously thought, and functionally link it to the checkpoint pathway.
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| 13. |
- Molin, Claes, 1977, et al.
(author)
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mRNA stability changes precede changes in steady-state mRNA amounts during hyperosmotic stress
- 2009
-
In: RNA. - : Cold Spring Harbor Laboratory. - 1355-8382 .- 1469-9001. ; 15:4, s. 600-614
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Journal article (peer-reviewed)abstract
- Under stress, cells need to optimize the activity of a wide range of gene products during the response phases: shock, adaptation, and recovery. This requires coordination of several levels of regulation, including turnover and translation efficiencies ofmRNAs. Mitogen-activated protein (MAP) kinase pathways are implicated in many aspects of the environmental stress response,including initiation of transcription, translation efficiency, and mRNA turnover. In this study, we analyze mRNA turnover ratesand mRNA steady-state levels at different time points following mild hyperosmotic shock in Saccharomyces cerevisiae cells. Theregulation of mRNA stability is transient and affects most genes for which there is a change in transcript level. These changesprecede and prepare for the changes in steady-state levels, both regarding the initial increase and the later decline of stressinducedmRNAs. The inverse is true for stress-repressed genes, which become stabilized during hyperosmotic stress inpreparation of an increase as the cells recover. The MAP kinase Hog1 affects both steady-state levels and stability of stressresponsivetranscripts, whereas Rck2 influences steady-state levels without a major effect on stability. Regulation of mRNAstability is a wide-spread, but not universal, effect on stress-responsive transcripts during transient hyperosmotic stress. Bydestabilizing stress-induced mRNAs when their steady-state levels have reached a maximum, the cell prepares for thesubsequent recovery phase when these transcripts are to return to normal levels. Conversely, stabilization of stress-repressedmRNAs permits their rapid accumulation in the recovery phase. Our results show that mRNA turnover is coordinated withtranscriptional induction.
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| 14. |
- Selpi, Selpi, 1977, et al.
(author)
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Predicting functional upstream open reading frames in Saccharomyces cerevisiae
- 2009
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In: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 10
-
Journal article (peer-reviewed)abstract
- Background: Some upstream open reading frames (uORFs) regulate gene expression (i.e., they are functional) and can play key roles in keeping organisms healthy. However, how uORFs are involved in gene regulation is not yet fully understood. In order to get a complete view of how uORFs are involved in gene regulation, it is expected that a large number of experimentally verified functional uORFs are needed. Unfortunately, wet-experiments to verify that uORFs are functional are expensive. Results: In this paper, a new computational approach to predicting functional uORFs in the yeast Saccharomyces cerevisiae is presented. Our approach is based on inductive logic programming and makes use of a novel combination of knowledge about biological conservation, Gene Ontology annotations and genes' responses to different conditions. Our method results in a set of simple and informative hypotheses with an estimated sensitivity of 76%. The hypotheses predict 301 further genes to have 398 novel functional uORFs. Three (RPC11, TPK1, and FOL1) of these 301 genes have been hypothesised, following wet-experiments, by a related study to have functional uORFs. A comparison with another related study suggests that eleven of the predicted functional uORFs from genes LDB17, HEM3, CIN8, BCK2, PMC1, FAS1, APP1, ACC1, CKA2, SUR1, and ATH1 are strong candidates for wet-lab experimental studies. Conclusions: Learning based prediction of functional uORFs can be done with a high sensitivity. The predictions made in this study can serve as a list of candidates for subsequent wet-lab verification and might help to elucidate the regulatory roles of uORFs.
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| 15. |
- Sunnerhagen, Per, 1959
(author)
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Cytoplasmatic post-transcriptional regulation and intracellular signalling
- 2007
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In: Mol Genet Genomics. ; 277:4, s. 341-55
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Research review (peer-reviewed)abstract
- Studies of intracellular signalling have traditionally focused on regulation at the levels of initiation of transcription on one hand, and post-translational regulation on the other. More recently, it is becoming apparent that the post-transcriptional level of gene expression is also subject to regulation by signalling pathways. The emphasis in this review is on short-term regulation of mRNAs at the levels of degradation and frequency of translation. Interplay between the mRNA translation and degradation machineries and mainly the TOR, stress-induced MAP kinase (SAPK), and DNA damage checkpoint pathways is discussed. Since a large fraction of the molecular mechanisms has been dissected using molecular genetics methods in yeast, most of the examples in this review are from budding and fission yeast. Some parallels are drawn to plant and animal cells. This review is intended for those more familiar with intracellular signalling, and who realise that post-transcriptional regulation may be an underemphasised level of signalling output.
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| 16. |
- Swaminathan, Swarna, 1975, et al.
(author)
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Degradation of Saccharomyces cervisiae Rck2 upon exposure of cells to high levels of zinc is dependent on Pep4
- 2005
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In: Molecular Genetics and Genomics. - : Springer Science and Business Media LLC. - 1617-4615 .- 1617-4623. ; 273:5, s. 433-9
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Journal article (peer-reviewed)abstract
- In undisturbed cells, the MAPK-activated protein kinase Rck2 of Saccharomyces cerevisiae is a stable protein with a turnover time exceeding 60 min. However, we have found that Rck2 is subject to intracellular degradation after exposure of cells to Zn2+ concentrations of 5 mM or more. In high-zinc medium, most of the Rck2 pool is degraded within 5 min. This degradation is blocked by inhibiting the vacuolar proteolytic pathway with the protease inhibitor phenyl methyl sulphonyl fluoride or by mutation of the PEP4 gene. By contrast, blocking the proteasomal pathway with the inhibitor MG132 does not prevent Rck2 degradation upon addition of Zn2+, nor is degradation inhibited in the proteasomal mutations pre1 pre2, cim3, or cim5. The stability of Rck2 is not affected by any of the other stress conditions examined, or by growth rate. Possible mechanisms of the degradation of Rck2 under high zinc conditions, and its physiological significance, are discussed.
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| 17. |
- Swaminathan, Swarna, 1975, et al.
(author)
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Rck2 is required for reprogramming of ribosomes during oxidative stress
- 2006
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In: Molecular Biology of the Cell. ; 17:3, s. 1472-1482
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Journal article (peer-reviewed)abstract
- Rck2 is a mitogen-activated protein kinase-activated protein kinase in yeast implicated in translational regulation. rck2Delta mutants are mildly sensitive to oxidative stress, a condition that causes dissociation of actively translating ribosomes (polysomes). In rck2Delta cells, polysomes are lost to an even higher degree than in the wild-type upon stress. Cells overexpressing the catalytically inactive rck2-kd allele are highly sensitive to oxidative stress. In such cells, dissociation of polysomes upon stress was instead greatly delayed. The protein synthesis rate decreased to a similar degree as in wild-type cells, however, indicating that in rck2-kd cells, the polysome complexes were inactive. Array analyses of total and polysome-associated mRNAs revealed major deregulation of the translational machinery in rck2 mutant cells. This involves transcripts for cytosolic ribosomal proteins and for processing and assembly of ribosomes. In rck2Delta cells, weakly transcribed mRNAs associate more avidly with polysomes than in wild-type cells, whereas the opposite holds true for rck2-kd cells. This is consistent with perturbed regulation of translation elongation, which is predicted to alter the ratio between mRNAs with and without strong entry sites at ribosomes. We infer that imbalances in the translational apparatus are a major reason for the inability of these cells to respond to stress.
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