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Byström, Anders
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Publications (10 of 52) Show all publications
Koshla, O., Yushchuk, O., Stash, I., Dacyuk, Y., Myronovskyi, M., Jäger, G., . . . Ostash, B. (2019). Gene miaA for post-transcriptional modification of tRNAXXA is important for morphological and metabolic differentiation in Streptomyces. Molecular Microbiology, 112(1), 249-265
Open this publication in new window or tab >>Gene miaA for post-transcriptional modification of tRNAXXA is important for morphological and metabolic differentiation in Streptomyces
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2019 (English)In: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 112, no 1, p. 249-265Article in journal (Refereed) Published
Abstract [en]

Members of actinobacterial genus Streptomyces possess a sophisticated life cycle and are the deepest source of bioactive secondary metabolites. Although morphogenesis and secondary metabolism are subject to transcriptional co-regulation, streptomycetes employ an additional mechanism to initiate the aforementioned processes. This mechanism is based on delayed translation of rare leucyl codon UUA by the only cognate tRNA(UAA)(Leu) (encoded by bldA). The bldA-based genetic switch is an extensively documented example of translational regulation in Streptomyces. Yet, after five decades since the discovery of bldA, factors that shape its function and peculiar conditionality remained elusive. Here we address the hypothesis that post-transcriptional tRNA modifications play a role in tRNA-based mechanisms of translational control in Streptomyces. Particularly, we studied two Streptomyces albus J1074 genes, XNR_1074 (miaA) and XNR_1078 (miaB), encoding tRNA (adenosine(37)-N6)-dimethylallyltransferase and tRNA (N6-isopentenyl adenosine(37)-C2)-methylthiotransferase respectively. These enzymes produce, in a sequential manner, a hypermodified ms(2)i(6)A37 residue in most of the A36-A37-containing tRNAs. We show that miaB and especially miaA null mutant of S. albus possess altered morphogenesis and secondary metabolism. We provide genetic evidence that miaA deficiency impacts translational level of gene expression, most likely through impaired decoding of codons UXX and UUA in particular.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-161841 (URN)10.1111/mmi.14266 (DOI)000474705900016 ()31017319 (PubMedID)
Available from: 2019-08-08 Created: 2019-08-08 Last updated: 2019-08-08Bibliographically approved
Bento-Abreu, A., Jager, G., Swinnen, B., Rué, L., Hendrickx, S., Jones, A., . . . Robberecht, W. (2018). Elongator subunit 3 (ELP3) modifies ALS through tRNA modification.. Human Molecular Genetics, 27(7), 1276-1289
Open this publication in new window or tab >>Elongator subunit 3 (ELP3) modifies ALS through tRNA modification.
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2018 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 7, p. 1276-1289Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder of which the progression is influenced by several disease-modifying factors. Here, we investigated ELP3, a subunit of the elongator complex that modifies tRNA wobble uridines, as one of such ALS disease modifiers. ELP3 attenuated the axonopathy of a mutant SOD1, as well as of a mutant C9orf72 ALS zebrafish model. Furthermore, the expression of ELP3 in the SOD1G93A mouse extended the survival and attenuated the denervation in this model. Depletion of ELP3 in vitro reduced the modified tRNA wobble uridine mcm5s2U and increased abundance of insoluble mutant SOD1, which was reverted by exogenous ELP3 expression. Interestingly, the expression of ELP3 in the motor cortex of ALS patients was reduced and correlated with mcm5s2U levels. Our results demonstrate that ELP3 is a modifier of ALS and suggest a link between tRNA modification and neurodegeneration.

Place, publisher, year, edition, pages
Oxford University Press, 2018
National Category
Cell Biology Neurosciences
Identifiers
urn:nbn:se:umu:diva-147873 (URN)10.1093/hmg/ddy043 (DOI)000429009400013 ()29415125 (PubMedID)
Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2018-06-27Bibliographically approved
Johansson, M. J., Xu, F. & Byström, A. S. (2018). Elongator-a tRNA modifying complex that promotes efficient translational decoding. Biochimica et Biophysica Acta, 1861(4), 401-408
Open this publication in new window or tab >>Elongator-a tRNA modifying complex that promotes efficient translational decoding
2018 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1861, no 4, p. 401-408Article in journal (Refereed) Published
Abstract [en]

Naturally occurring modifications of the nucleosides in the anticodon region of tRNAs influence their translational decoding properties. Uridines present at the wobble position in eukaryotic cytoplasmic tRNAs often contain a 5-carbamoylmethyl (ncm5) or 5-methoxycarbonylmethyl (mcm5) side-chain and sometimes also a 2-thio or 2'-O-methyl group. The first step in the formation of the ncm5 and mcm5 side-chains requires the conserved six-subunit Elongator complex. Although Elongator has been implicated in several different cellular processes, accumulating evidence suggests that its primary, and possibly only, cellular function is to promote modification of tRNAs. In this review, we discuss the biosynthesis and function of modified wobble uridines in eukaryotic cytoplasmic tRNAs, focusing on the in vivo role of Elongator-dependent modifications in Saccharomyces cerevisiae. 

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-147685 (URN)10.1016/j.bbagrm.2017.11.006 (DOI)000430523900013 ()29170010 (PubMedID)
Funder
Swedish Research Council, 621-2016-03949
Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2018-06-09Bibliographically approved
Xu, F., Zhou, Y., Byström, A. & Johansson, M. J. O. (2018). Identification of factors that promote biogenesis of tRNACGASer.. RNA Biology, 15(10), 1286-1294
Open this publication in new window or tab >>Identification of factors that promote biogenesis of tRNACGASer.
2018 (English)In: RNA Biology, ISSN 1547-6286, E-ISSN 1555-8584, Vol. 15, no 10, p. 1286-1294Article in journal (Refereed) Published
Abstract [en]

A wide variety of factors are required for the conversion of pre-tRNA molecules into the mature tRNAs that function in translation. To identify factors influencing tRNA biogenesis, we previously performed a screen for strains carrying mutations that induce lethality when combined with a sup61-T47:2C allele, encoding a mutant form of tRNACGASer. Analyzes of two complementation groups led to the identification of Tan1 as a protein involved in formation of the modified nucleoside N4-acetylcytidine (ac4C) in tRNA and Bud13 as a factor controlling the levels of ac4C by promoting TAN1 pre-mRNA splicing. Here, we describe the remaining complementation groups and show that they include strains with mutations in genes for known tRNA biogenesis factors that modify (DUS2, MOD5 and TRM1), transport (LOS1), or aminoacylate (SES1) tRNACGASer. Other strains carried mutations in genes for factors involved in rRNA/mRNA synthesis (RPA49, RRN3 and MOT1) or magnesium uptake (ALR1). We show that mutations in not only DUS2, LOS1 and SES1 but also in RPA49, RRN3 and MOT1 cause a reduction in the levels of the altered tRNACGASer. These results indicate that Rpa49, Rrn3 and Mot1 directly or indirectly influence tRNACGASer biogenesis.

Place, publisher, year, edition, pages
Taylor & Francis, 2018
Keywords
modified nucleosides, sup61, tRNA maturation, tRNA modification, tRNASer
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-154010 (URN)10.1080/15476286.2018.1526539 (DOI)000450608900004 ()30269676 (PubMedID)
Funder
Magnus Bergvall Foundation, 2017-02098Swedish Research Council, 621-2016-03949
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-12Bibliographically approved
Tükenmez, H., Magnussen, H., Kovermann, M., Byström, A. & Wolf-Watz, M. (2016). Linkage between Fitness of Yeast Cells and Adenylate Kinase Catalysis. PLoS ONE, 11(9), Article ID e0163115.
Open this publication in new window or tab >>Linkage between Fitness of Yeast Cells and Adenylate Kinase Catalysis
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, article id e0163115Article in journal (Refereed) Published
Abstract [en]

Enzymes have evolved with highly specific values of their catalytic parameters kcat and KM. This poses fundamental biological questions about the selection pressures responsible for evolutionary tuning of these parameters. Here we are address these questions for the enzyme adenylate kinase (Adk) in eukaryotic yeast cells. A plasmid shuffling system was developed to allow quantification of relative fitness (calculated from growth rates) of yeast in response to perturbations of Adk activity introduced through mutations. Biophysical characterization verified that all variants studied were properly folded and that the mutations did not cause any substantial differences to thermal stability. We found that cytosolic Adk is essential for yeast viability in our strain background and that viability could not be restored with a catalytically dead, although properly folded Adk variant. There exist a massive overcapacity of Adk catalytic activity and only 12% of the wild type kcat is required for optimal growth at the stress condition 20°C. In summary, the approach developed here has provided new insights into the evolutionary tuning of kcat for Adk in a eukaryotic organism. The developed methodology may also become useful for uncovering new aspects of active site dynamics and also in enzyme design since a large library of enzyme variants can be screened rapidly by identifying viable colonies.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-125853 (URN)10.1371/journal.pone.0163115 (DOI)000383891900032 ()27642758 (PubMedID)
Funder
Swedish Research Council, 621-2013-5954Swedish Research Council, 621-2012-3576
Available from: 2016-09-20 Created: 2016-09-20 Last updated: 2018-06-07Bibliographically approved
Karlsborn, T., Mahmud, A. K., Tükenmez, H. & Byström, A. S. (2016). Loss of ncm5 and mcm5 wobble uridine side chains results in an altered metabolic profile. Metabolomics, 12(12), Article ID 177.
Open this publication in new window or tab >>Loss of ncm5 and mcm5 wobble uridine side chains results in an altered metabolic profile
2016 (English)In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 12, no 12, article id 177Article in journal (Refereed) Published
Abstract [en]

Introduction: The Elongator complex, comprising six subunits (Elp1p-Elp6p), is required for formation of 5-carbamoylmethyl (ncm(5)) and 5-methoxycarbonylmethyl (mcm(5)) side chains on wobble uridines in 11 out of 42 tRNA species in Saccharomyces cerevisiae. Loss of these side chains reduces the efficiency of tRNA decoding during translation, resulting in pleiotropic phenotypes. Overexpression of hypomodified tRNA(s2UUU)(Lys); tRNA(s2UUG)(Gln) and tRNA(s2UUC)(Glu), which in wild-type strains are modified with mcm(5)s(2)U, partially suppress phenotypes of an elp3 Delta strain. Objectives: To identify metabolic alterations in an elp3 Delta strain and elucidate whether these metabolic alterations are suppressed by overexpression of hypomodified tRNA(s2UUU)(Lys); tRNA(s2UUG)(Gln) and tRNA(s2UUC)(Glu). Method: Metabolic profiles were obtained using untargeted GC-TOF-MS of a temperature-sensitive elp3 Delta strain carrying either an empty low-copy vector, an empty high-copy vector, a low-copy vector harboring the wild-type ELP3 gene, or a high-copy vector overexpressing tRNA(s2UUU)(Lys); tRNA(s2UUG)(Gln) and tRNA(s2UUC)(Glu). The temperature sensitive elp3 Delta strain derivatives were cultivated at permissive (30 degrees C) or semi-permissive (34 degrees C) growth conditions. Results: Culturing an elp3 Delta strain at 30 or 34 degrees C resulted in altered metabolism of 36 and 46 %, respectively, of all metabolites detected when compared to an elp3D strain carrying the wild-type ELP3 gene. Overexpression of hypomodified tRNA(s2UUU)(Lys); tRNA(s2UUG)(Gln) and tRNA(s2UUC)(Glu) suppressed a subset of the metabolic alterations observed in the elp3 Delta strain. Conclusion: Our results suggest that the presence of ncm(5)- and mcm(5)-side chains on wobble uridines in tRNA are important for metabolic homeostasis.

Place, publisher, year, edition, pages
Springer, 2016
Keywords
Elongator complex, tRNA wobble uridine modifications, Translation, ELP3, Metabolomics, Metabolic profiling
National Category
Biochemistry and Molecular Biology Endocrinology and Diabetes
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-125635 (URN)10.1007/s11306-016-1120-8 (DOI)000389604300002 ()27738410 (PubMedID)
Available from: 2016-09-13 Created: 2016-09-13 Last updated: 2018-06-07Bibliographically approved
Macari, F., El-houfi, Y., Boldina, G., Xu, H., Khoury-Hanna, S., Ollier, J., . . . Joubert, D. (2016). TRM6/61 connects PKCα with translational control through tRNAiMet stabilization: impact on tumorigenesis. Oncogene, 35(14), 1785-1796
Open this publication in new window or tab >>TRM6/61 connects PKCα with translational control through tRNAiMet stabilization: impact on tumorigenesis
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2016 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 35, no 14, p. 1785-1796Article in journal (Refereed) Published
Abstract [en]

Accumulating evidence suggests that changes of the protein synthesis machinery alter translation of specific mRNAs and participate in malignant transformation. Here we show that protein kinase C [alpha] (PKC[alpha]) interacts with TRM61, the catalytic subunit of the TRM6/61 tRNA methyltransferase. The TRM6/61 complex is known to methylate the adenosine 58 of the initiator methionine tRNA (tRNAiMet), a nuclear post-transcriptional modification associated with the stabilization of this crucial component of the translation-initiation process. Depletion of TRM6/61 reduced proliferation and increased death of C6 glioma cells, effects that can be partially rescued by overexpression of tRNAiMet. In contrast, elevated TRM6/61 expression regulated the translation of a subset of mRNAs encoding proteins involved in the tumorigenic process and increased the ability of C6 cells to form colonies in soft agar or spheres when grown in suspension. In TRM6/61/tRNAiMet-overexpressing cells, PKC[alpha] overexpression decreased tRNAiMet expression and both colony- and sphere-forming potentials. A concomitant increase in TRM6/TRM61 mRNA and tRNAiMet expression with decreased expression of PKC[alpha] mRNA was detected in highly aggressive glioblastoma multiforme as compared with Grade II/III glioblastomas, highlighting the clinical relevance of our findings. Altogether, we suggest that PKC[alpha] tightly controls TRM6/61 activity to prevent translation deregulation that would favor neoplastic development.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-109854 (URN)10.1038/onc.2015.244 (DOI)000373610400005 ()26234676 (PubMedID)
Note

Supplementary information available for this article at http://www.nature.com/onc/journal/vaop/ncurrent/suppinfo/onc2015244s1.html

Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2018-06-07Bibliographically approved
Leitner, J., Retzer, K., Malenica, N., Bartkeviciute, R., Lucyshyn, D., Jäger, G., . . . Luschnig, C. (2015). Meta-regulation of Arabidopsis Auxin Responses Depends on tRNA Maturation. Cell reports, 11(4), 516-526
Open this publication in new window or tab >>Meta-regulation of Arabidopsis Auxin Responses Depends on tRNA Maturation
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2015 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 11, no 4, p. 516-526Article in journal (Refereed) Published
Abstract [en]

Polar transport of the phytohormone auxin throughout plants shapes morphogenesis and is subject to stringent and specific control. Here, we identify basic cellular activities connected to translational control of gene expression as sufficient to specify auxin-mediated development. Mutants in subunits of Arabidopsis Elongator, a protein complex modulating translational efficiency via maturation of tRNAs, exhibit defects in auxin-controlled developmental processes, associated with reduced abundance of PIN-formed (PIN) auxin transport proteins. Similar anomalies are observed upon interference with tRNA splicing by downregulation of RNA ligase (AtRNL), pointing to a general role of tRNA maturation in auxin signaling. Elongator Protein 6 (ELP6) and AtRNL expression patterns underline an involvement in adjusting PIN protein levels, whereas rescue of mutant defects by auxin indicates rate-limiting activities in auxin-controlled organogenesis. This emphasizes mechanisms in which auxin serves as a bottleneck for plant morphogenesis, translating common cellular activities into defined developmental readouts.

National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-106287 (URN)10.1016/j.celrep.2015.03.054 (DOI)000353902600003 ()25892242 (PubMedID)
Available from: 2015-07-10 Created: 2015-07-09 Last updated: 2018-06-07Bibliographically approved
Tükenmez, H., Xu, H., Esberg, A. & Byström, A. S. (2015). The role of wobble uridine modifications in +1 translational frameshifting in eukaryotes. Nucleic Acids Research, 43(19), 9489-9499
Open this publication in new window or tab >>The role of wobble uridine modifications in +1 translational frameshifting in eukaryotes
2015 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 43, no 19, p. 9489-9499Article in journal (Refereed) Published
Abstract [en]

In Saccharomyces cerevisiae, 11 out of 42 tRNA species contain 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U), 5-methoxycarbonylmethyluridine (mcm5U), 5-carbamoylmethyluridine (ncm5U) or 5-carbamoylmethyl-2′-O-methyluridine (ncm5Um) nucleosides in the anticodon at the wobble position (U34). Earlier we showed that mutants unable to form the side chain at position 5 (ncm5 or mcm5) or lacking sulphur at position 2 (s2) of U34 result in pleiotropic phenotypes, which are all suppressed by overexpression of hypomodified tRNAs. This observation suggests that the observed phenotypes are due to inefficient reading of cognate codons or an increased frameshifting. The latter may be caused by a ternary complex (aminoacyl-tRNA*eEF1A*GTP) with a modification deficient tRNA inefficiently being accepted to the ribosomal A-site and thereby allowing an increased peptidyl-tRNA slippage and thus a frameshift error. In this study, we have investigated the role of wobble uridine modifications in reading frame maintenance, using either the Renilla/Firefly luciferase bicistronic reporter system or a modified Ty1 frameshifting site in a HIS4A::lacZ reporter system. We here show that the presence of mcm5 and s2 side groups at wobble uridines are important for reading frame maintenance and thus the aforementioned mutant phenotypes might partly be due to frameshift errors.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-109852 (URN)10.1093/nar/gkv832 (DOI)000366405600036 ()
Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2018-06-07Bibliographically approved
Xu, H., Bygdell, J., Wingsle, G. & Byström, A. S. (2015). Yeast Elongator protein Elp1p does not undergo proteolytic processing in exponentially growing cells. MicrobiologyOpen, 4(6), 867-878
Open this publication in new window or tab >>Yeast Elongator protein Elp1p does not undergo proteolytic processing in exponentially growing cells
2015 (English)In: MicrobiologyOpen, ISSN 2045-8827, E-ISSN 2045-8827, Vol. 4, no 6, p. 867-878Article in journal (Refereed) Published
Abstract [en]

In eukaryotic organisms, Elongator is a six-subunit protein complex required for the formation of 5-carbamoylmethyl (ncm5) and 5-methylcarboxymethyl (mcm5) side chains on uridines present at the wobble position (U34) of tRNA. The open reading frame encoding the largest Elongator subunit Elp1p has two in-frame 5′ AUG methionine codons separated by 48 nucleotides. Here, we show that the second AUG acts as the start codon of translation. Furthermore, Elp1p was previously shown to exist in two major forms of which one was generated by proteolysis of full-length Elp1p and this proteolytic cleavage was suggested to regulate Elongator complex activity. In this study, we found that the vacuolar protease Prb1p was responsible for the cleavage of Elp1p. The cleavage occurs between residues 203 (Lys) and 204 (Ala) as shown by amine reactive Tandem Mass Tag followed by LC-MS/MS (liquid chromatography mass spectrometry) analysis. However, using a modified protein extraction procedure, including trichloroacetic acid, only full-length Elp1p was observed, showing that truncation of Elp1p is an artifact occurring during protein extraction. Consequently, our results indicate that N-terminal truncation of Elp1p is not likely to regulate Elongator complex activity.

Keywords
Elongator complex, Elp1p, Prb1p, proteolysis, Saccharomyces cerevisiae, tRNA modification
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-109853 (URN)10.1002/mbo3.285 (DOI)000368415300002 ()26407534 (PubMedID)
Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2018-06-07Bibliographically approved
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