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  • 151. Sterky, F
    et al.
    Regan, S
    Karlsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Hertzberg, M
    Rohde, A
    Holmberg, A
    Amini, B
    Bhalerao, R
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Larsson, M
    Villarroel, R
    Van Montagu, M
    Sandberg, G
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Olsson, O
    Teeri, T T
    Boerjan, W
    Gustafsson, Petter
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Uhlen, M
    Sundberg, B
    Lundeberg, J
    Gene discovery in the wood-forming tissues of poplar: Analysis of 5,692 expressed sequence tags1998In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, no 22, p. 13330-13335Article in journal (Refereed)
    Abstract [en]

    A rapidly growing area of genome research is the generation of expressed sequence tags (ESTs) in which large numbers of randomly selected cDNA clones are partially sequenced. The collection of ESTs reflects the level and complexity of gene expression in the sampled tissue, To date, the majority of plant ESTs are from nonwoody plants such as Arabidopsis, Brassica, maize, and rice. Here, we present a large-scale production of ESTs from the wood-forming tissues of two poplars, Populus tremula L, x tremuloides Michx, and Populus trichocarpa 'Trichobel.' The 5,692 ESTs analyzed represented a total of 3,719 unique transcripts for the two cDNA libraries, Putative functions could be assigned to 2,245 of these transcripts that corresponded to 820 protein functions. Of specific interest to forest biotechnology are the 4% of ESTs involved in various processes of cell wall formation, such as lignin and cellulose synthesis, 5% similar to developmental regulators and members of known signal transduction pathways, and 2% involved in hormone biosynthesis. An additional 12% of the ESTs show ed no significant similarity to any other DNA or protein sequences in existing databases. The absence of these sequences from public databases may indicate a specific role for these proteins in wood formation. The cDNA libraries and the accompanying database are valuable resources for forest research directed toward understanding the genetic control of wood formation and future endeavors to modify wood and fiber properties for industrial use.

  • 152.
    Sukonina, Valentina
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Physiological chemistry.
    Lookene, Aivar
    Olivecrona, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Physiological chemistry.
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Medical Biosciences, Physiological chemistry.
    Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue.2006In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 46, p. 17450-17455Article in journal (Refereed)
  • 153. Torregrosa-Muñumer, Rubén
    et al.
    Forslund, Josefin M. E.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Goffart, Steffi
    Pfeiffer, Annika
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Stojkovič, Gorazd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Carvalho, Gustavo
    Al-Furoukh, Natalie
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Blanco, Luis
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pohjoismäki, Jaakko L. O.
    PrimPol is required for replication reinitiation after mtDNA damage2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 43, p. 11398-11403Article in journal (Refereed)
    Abstract [en]

    Eukaryotic PrimPol is a recently discovered DNA-dependent DNA primase and translesion synthesis DNA polymerase found in the nucleus and mitochondria. Although PrimPol has been shown to be required for repriming of stalled replication forks in the nucleus, its role in mitochondria has remained unresolved. Here we demonstrate in vivo and in vitro that PrimPol can reinitiate stalled mtDNA replication and can prime mtDNA replication from nonconventional origins. Our results not only help in the understanding of how mitochondria cope with replicative stress but can also explain some controversial features of the lagging-strand replication.

  • 154. Vain, Thomas
    et al.
    Raggi, Sara
    Ferro, Noel
    Barange, Deepak Kumar
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Chemical Biology Umeå, Chemical Biology Consortium Sweden.
    Kieffer, Martin
    Ma, Qian
    Doyle, Siamsa M.
    Thelander, Mattias
    Pařízková, Barbora
    Novák, Ondřej
    Ismail, Alexandre
    Enquist, Per-Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Chemical Biology Umeå, Chemical Biology Consortium Sweden.
    Rigal, Adeline
    Łangowska, Małgorzata
    Ramans Harborough, Sigurd
    Zhang, Yi
    Ljung, Karin
    Callis, Judy
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Chemical Biology Umeå, Chemical Biology Consortium Sweden.
    Kepinski, Stefan
    Estelle, Mark
    Pauwels, Laurens
    Robert, Stéphanie
    Selective auxin agonists induce specific AUX/IAA protein degradation to modulate plant development2019In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 13, p. 6463-6472Article in journal (Refereed)
    Abstract [en]

    The plant hormone auxin coordinates almost all aspects of plant development. Throughout plant life, the expression of hundreds of genes involved in auxin regulation is orchestrated via several combinatorial and cell-specific auxin perception systems. An effective approach to dissect these complex pathways is the use of synthetic molecules that target specific processes of auxin activity. Here, we describe synthetic auxins, RubNeddins (RNs), which act as selective auxin agonists. The RN with the greatest potential for dissecting auxin perception was RN4, which we used to reveal a role for the chromatin remodeling ATPase BRAHMA in apical hook development. Therefore, the understanding of RN mode of action paves the way to dissecting specific molecular components involved in auxin-regulated developmental processes.Auxin phytohormones control most aspects of plant development through a complex and interconnected signaling network. In the presence of auxin, AUXIN/INDOLE-3-ACETIC ACID (AUX/IAA) transcriptional repressors are targeted for degradation by the SKP1-CULLIN1-F-BOX (SCF) ubiquitin-protein ligases containing TRANSPORT INHIBITOR RESISTANT 1/AUXIN SIGNALING F-BOX (TIR1/AFB). CULLIN1-neddylation is required for SCFTIR1/AFB functionality, as exemplified by mutants deficient in the NEDD8-activating enzyme subunit AUXIN-RESISTANT 1 (AXR1). Here, we report a chemical biology screen that identifies small molecules requiring AXR1 to modulate plant development. We selected four molecules of interest, RubNeddin 1 to 4 (RN1 to -4), among which RN3 and RN4 trigger selective auxin responses at transcriptional, biochemical, and morphological levels. This selective activity is explained by their ability to consistently promote the interaction between TIR1 and a specific subset of AUX/IAA proteins, stimulating the degradation of particular AUX/IAA combinations. Finally, we performed a genetic screen using RN4, the RN with the greatest potential for dissecting auxin perception, which revealed that the chromatin remodeling ATPase BRAHMA is implicated in auxin-mediated apical hook development. These results demonstrate the power of selective auxin agonists to dissect auxin perception for plant developmental functions, as well as offering opportunities to discover new molecular players involved in auxin responses.

    The full text will be freely available from 2019-09-26 11:52
  • 155.
    Vaitkevicius, Karolis
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lindmark, Barbro
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ou, Gangwei
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Song, Tianyan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Toma, Claudia
    Division of Bacterial Pathogenesis, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
    Iwanaga, Masaaki
    Division of Bacterial Pathogenesis, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.
    Zhu, Jun
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia.
    Andersson, Agneta
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Marine Sciences Centre (UMF).
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Tuck, Simon
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    A Vibrio cholerae protease needed for killing of Caenorhabditis elegans has a role in protection from natural predator grazing2006In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 24, p. 9280-9285Article in journal (Refereed)
    Abstract [en]

    Vibrio cholerae is the causal bacterium of the diarrheal disease cholera, and its growth and survival are thought to be curtailed by bacteriovorous predators, e.g., ciliates and flagellates. We explored Caenorhabditis elegans as a test organism after finding that V. cholerae can cause lethal infection of this nematode. By reverse genetics we identified an extracellular protease, the previously uncharacterized PrtV protein, as being necessary for killing. The killing effect is associated with the colonization of bacteria within the Caenorhabditis elegans intestine. We also show that PrtV is essential for V. cholerae in the bacterial survival from grazing by the flagellate Cafeteria roenbergensis and the ciliate Tetrahymena pyriformis. The PrtV protein appears to have an indirect role in the interaction of V. cholerae with mammalian host cells as judged from tests with tight monolayers of human intestinal epithelial cells. Our results demonstrate a key role for PrtV in V. cholerae interaction with grazing predators, and we establish Caenorhabditis elegans as a convenient organism for identification of V. cholerae factors involved in host interactions and environmental persistence.

  • 156. Voon, Chia Pao
    et al.
    Guan, Xiaoqian
    Sun, Yuzhe
    Sahu, Abira
    Chan, May Ngor
    Gardeström, Per
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Wagner, Stephan
    Fuchs, Philippe
    Nietzel, Thomas
    Versaw, Wayne K.
    Schwarzländer, Markus
    Lim, Boon Leong
    ATP compartmentation in plastids and cytosol of Arabidopsis thaliana revealed by fluorescent protein sensing2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 45, p. E10778-E10787Article in journal (Refereed)
    Abstract [en]

    Matching ATP: NADPH provision and consumption in the chloroplast is a prerequisite for efficient photosynthesis. In terms of ATP: NADPH ratio, the amount of ATP generated from the linear electron flow does not meet the demand of the Calvin-Benson-Bassham (CBB) cycle. Several different mechanisms to increase ATP availability have evolved, including cyclic electron flow in higher plants and the direct import of mitochondrial-derived ATP in diatoms. By imaging a fluorescent ATP sensor protein expressed in living Arabidopsis thaliana seedlings, we found that MgATP(2-) concentrations were lower in the stroma of mature chloroplasts than in the cytosol, and exogenous ATP was able to enter chloroplasts isolated from 4- and 5-day-old seedlings, but not chloroplasts isolated from 10- or 20-day-old photosynthetic tissues. This observation is in line with the previous finding that the expression of chloroplast nucleotide transporters (NTTs) in Arabidopsis mesophyll is limited to very young seedlings. Employing a combination of photosynthetic and respiratory inhibitors with compartment-specific imaging of ATP, we corroborate the dependency of stromal ATP production on mitochondrial dissipation of photosynthetic reductant. Our data suggest that, during illumination, the provision and consumption of ATP: NADPH in chloroplasts can be balanced by exporting excess reductants rather than importing ATP from the cytosol.

  • 157. Walhovd, Kristine B.
    et al.
    Krogsrud, Stine K.
    Amlien, Inge K.
    Bartsch, Hauke
    Bjornerud, Atle
    Due-Tonnessen, Paulina
    Grydeland, Hakon
    Hagler, Donald J., Jr.
    Haberg, Asta K.
    Kremen, William S.
    Ferschmann, Lia
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Univ Oslo, Dept Psychol, Res Grp Lifespan Changes Brain & Cognit, N-0373 Oslo, Norway.
    Panizzon, Matthew S.
    Rohani, Darius A.
    Skranes, Jon
    Storsve, Andreas B.
    Solsnes, Anne Elisabeth
    Tamnes, Christian K.
    Thompson, Wesley K.
    Reuter, Chase
    Dale, Anders M.
    Fjell, Anders M.
    Neurodevelopmental origins of lifespan changes in brain and cognition2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 33, p. 9357-9362Article in journal (Refereed)
    Abstract [en]

    Neurodevelopmental origins of functional variation in older age are increasingly being acknowledged, but identification of how early factors impact human brain and cognition throughout life has remained challenging. Much focus has been on age-specific mechanisms affecting neural foundations of cognition and their change. In contrast to this approach, we tested whether cerebral correlates of general cognitive ability (GCA) in development could be extended to the rest of the lifespan, and whether early factors traceable to prenatal stages, such as birth weight and parental education, may exert continuous influences. We measured the area of the cerebral cortex in a longitudinal sample of 974 individuals aged 4-88 y (1,633 observations). An extensive cortical region was identified wherein area related positively to GCA in development. By tracking area of the cortical region identified in the child sample throughout the lifespan, we showed that the cortical change trajectories of higher and lower GCA groups were parallel through life, suggesting continued influences of early life factors. Birth weight and parental education obtained from the Norwegian Mother-Child Cohort study were identified as such early factors of possible lifelong influence. Support for a genetic component was obtained in a separate twin sample (Vietnam Era Twin Study of Aging), but birth weight in the child sample had an effect on cortical area also when controlling for possible genetic differences in terms of parental height. Our results provide novel evidence for stability in brain-cognition relationships throughout life, and indicate that early life factors impact brain and cognition for the entire life course.

  • 158.
    Wandzioch, Ewa
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Kolterud, Åsa
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Jacobsson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Friedman, Scott L
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lhx2-/- mice develop liver fibrosis2004In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 47, p. 16549-16554Article in journal (Refereed)
    Abstract [en]

    Liver fibrosis is a wound-healing response to chronic injury of any type and is characterized by a progressive increase in deposition of extracellular matrix (ECM) proteins, the major source of which are activated hepatic stellate cells (HSCs). Because the LIM homeobox gene Lhx2 is expressed in HSCs and liver development in Lhx2 / mice is disrupted, we analyzed liver development in Lhx2 / embryos in detail. Lhx2 / embryos contain numerous activated HSCs and display a progressively increased deposition of the ECM proteins associated with liver fibrosis, suggesting that Lhx2 inhibits HSC activation. Transfection of Lhx2 cDNA into a human HSC line down-regulates expression of genes characteristic of activated HSCs. Moreover, the Lhx2 / liver display a disrupted cellular organization and an altered gene expression pattern of the intrahepatic endodermal cells, and the increased deposition of ECM proteins precedes these abnormalities. Collectively these results show that Lhx2 negatively regulates HSC activation, and its inactivation in developing HSCs appears therefore to mimic the signals that are triggered by the wound-healing response to chronic liver injury. This study establishes a spontaneous and reproducible animal model for hepatic fibrosis and reveals that Lhx2 expression in HSCs is important for proper cellular organization and differentiation of the liver.

  • 159.
    Wanrooij, Paulina H.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Engqvist, Martin K. M.
    Forslund, Josefin M. E.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Navarrete, Clara
    Nilsson, Anna Karin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sedman, Juhan
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Clausen, Anders R.
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Ribonucleotides incorporated by the yeast mitochondrial DNA polymerase are not repaired2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 47, p. 12466-12471, article id 201713085Article in journal (Refereed)
    Abstract [en]

    Incorporation of ribonucleotides into DNA during genome replication is a significant source of genomic instability. The frequency of ribonucleotides in DNA is determined by deoxyribonucleoside triphosphate/ribonucleoside triphosphate (dNTP/rNTP) ratios, by the ability of DNA polymerases to discriminate against ribonucleotides, and by the capacity of repair mechanisms to remove incorporated ribonucleotides. To simultaneously compare how the nuclear and mitochondrial genomes incorporate and remove ribonucleotides, we challenged these processes by changing the balance of cellular dNTPs. Using a collection of yeast strains with altered dNTP pools, we discovered an inverse relationship between the concentration of individual dNTPs and the amount of the corresponding ribonucleotides incorporated in mitochondrial DNA, while in nuclear DNA the ribonucleotide pattern was only altered in the absence of ribonucleotide excision repair. Our analysis uncovers major differences in ribonucleotide repair between the two genomes and provides concrete evidence that yeast mitochondria lack mechanisms for removal of ribonucleotides incorporated by the mtDNA polymerase. Furthermore, as cytosolic dNTP pool imbalances were transmitted equally well into the nucleus and the mitochondria, our results support a view of the cytosolic and mitochondrial dNTP pools in frequent exchange.

  • 160. Wenig, Katja
    et al.
    Chatwell, Lorenz
    von Pawel-Rammingen, Ulrich
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Björck, Lars
    Huber, Robert
    Sondermann, Peter
    Structure of the streptococcal endopeptidase IdeS, a cysteine proteinase with strict specificity for IgG.2004In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 50, p. 17371-17376Article in journal (Refereed)
    Abstract [en]

    Pathogenic bacteria have developed complex and diverse virulence mechanisms that weaken or disable the host immune defense system. IdeS (IgG-degrading enzyme of Streptococcus pyogenes) is a secreted cysteine endopeptidase from the human pathogen S. pyogenes with an extraordinarily high degree of substrate specificity, catalyzing a single proteolytic cleavage at the lower hinge of human IgG. This proteolytic degradation promotes inhibition of opsonophagocytosis and interferes with the killing of group A Streptococcus. We have determined the crystal structure of the catalytically inactive mutant IdeS-C94S by x-ray crystallography at 1.9-A resolution. Despite negligible sequence homology to known proteinases, the core of the structure resembles the canonical papain fold although with major insertions and a distinct substrate-binding site. Therefore IdeS belongs to a unique family within the CA clan of cysteine proteinases. Based on analogy with inhibitor complexes of papain-like proteinases, we propose a model for substrate binding by IdeS.

  • 161.
    Werner, Thomas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Liu, Gang
    Kang, Daiwu
    Ekengren, Sophia
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Steiner, Håkan
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    A family of peptidoglycan recognition proteins in the fruit fly Drosophila melanogaster.2000In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 97, no 25, p. 13772-13777Article in journal (Refereed)
    Abstract [en]

    Peptidoglycans from bacterial cell walls trigger immune responses in insects and mammals. A peptidoglycan recognition protein, PGRP, has been cloned from moths as well as vertebrates and has been shown to participate in peptidoglycan-mediated activation of prophenoloxidase in the silk moth. Here we report that Drosophila expresses 12 PGRP genes, distributed in 8 chromosomal loci on the 3 major chromosomes. By analyzing cDNA clones and genomic databases, we grouped them into two classes: PGRP-SA, SB1, SB2, SC1A, SC1B, SC2, and SD, with short transcripts and short 5'-untranslated regions; and PGRP-LA, LB, LC, LD, and LE, with long transcripts and long 5'-untranslated regions. The predicted structures indicate that the first group encodes extracellular proteins and the second group, intracellular and membrane-spanning proteins. Most PGRP genes are expressed in all postembryonic stages. Peptidoglycan injections strongly induce five of the genes. Transcripts from the different PGRP genes were found in immune competent organs such as fat body, gut, and hemocytes. We demonstrate that at least PGRP-SA and SC1B can bind peptidoglycan, and a function in immunity is likely for this family.

  • 162.
    Williams, Lindsey N
    et al.
    Department of Pathology, University of Washington, Seattle, WA 98195, USA.
    Marjavaara, Lisette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Knowels, Gary M
    Department of Pathology, University of Washington, Seattle, WA 98195, USA.
    Schultz, Eric M
    Department of Pathology, University of Washington, Seattle, WA 98195, USA.
    Fox, Edward J
    Department of Pathology, University of Washington, Seattle, WA 98195, USA.
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Herr, Alan J
    Department of Pathology, University of Washington, Seattle, WA 98195, USA.
    dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase ε variants2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 19, p. E2457-E2466Article in journal (Refereed)
    Abstract [en]

    Mutator phenotypes create genetic diversity that fuels tumor evolution. DNA polymerase (Pol) ε mediates leading strand DNA replication. Proofreading defects in this enzyme drive a number of human malignancies. Here, using budding yeast, we show that mutator variants of Pol ε depend on damage uninducible (Dun)1, an S-phase checkpoint kinase that maintains dNTP levels during a normal cell cycle and up-regulates dNTP synthesis upon checkpoint activation. Deletion of DUN1 (dun1Δ) suppresses the mutator phenotype of pol2-4 (encoding Pol ε proofreading deficiency) and is synthetically lethal with pol2-M644G (encoding altered Pol ε base selectivity). Although pol2-4 cells cycle normally, pol2-M644G cells progress slowly through S-phase. The pol2-M644G cells tolerate deletions of mediator of the replication checkpoint (MRC) 1 (mrc1Δ) and radiation sensitive (Rad) 9 (rad9Δ), which encode mediators of checkpoint responses to replication stress and DNA damage, respectively. The pol2-M644G mutator phenotype is partially suppressed by mrc1Δ but not rad9Δ; neither deletion suppresses the pol2-4 mutator phenotype. Thus, checkpoint activation augments the Dun1 effect on replication fidelity but is not required for it. Deletions of genes encoding key Dun1 targets that negatively regulate dNTP synthesis, suppress the dun1Δ pol2-M644G synthetic lethality and restore the mutator phenotype of pol2-4 in dun1Δ cells. DUN1 pol2-M644G cells have constitutively high dNTP levels, consistent with checkpoint activation. In contrast, pol2-4 and POL2 cells have similar dNTP levels, which decline in the absence of Dun1 and rise in the absence of the negative regulators of dNTP synthesis. Thus, dNTP pool levels correlate with Pol ε mutator severity, suggesting that treatments targeting dNTP pools could modulate mutator phenotypes for therapy.

  • 163. Wong, Alex
    et al.
    Albright, Shannon N
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Wolfner, Mariana F
    Evidence for structural constraint on ovulin, a rapidly evolving Drosophila melanogaster seminal protein.2006In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 49, p. 18644-9Article in journal (Refereed)
    Abstract [en]

    The egg-laying hormone ovulin (Acp26Aa) is among the most rapidly evolving proteins in the Drosophila genome. Against the background of ovulin's high sequence variability within and between species, we have identified highly conserved motifs that may play an important structural role. Using yeast two-hybrid and GST-pull-down assays, we show that ovulin interacts with itself. The C terminus of ovulin is necessary and sufficient for self-interaction, with its C-terminal 45 aa playing a major role. Under nonreducing conditions, ovulin participates in a high-molecular-mass complex, suggesting that it occurs in an oligomeric form. One or more of three predicted coiled-coil domains in the C terminus of ovulin may be involved in its self-interaction. These structural elements are conserved between species despite an overall rapid pace of evolution in ovulin's primary sequence. We therefore suggest that domains involved in ovulin's self-interaction form a conserved structural backbone for the protein, resulting in greater evolutionary flexibility at other sites.

  • 164. Xu, Jianfeng
    et al.
    Zheng, Siqun Lilly
    Isaacs, Sarah D
    Wiley, Kathleen E
    Wiklund, Fredrik
    Sun, Jielin
    Kader, A Karim
    Li, Ge
    Purcell, Lina D
    Kim, Seong-Tae
    Hsu, Fang-Chi
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Hugosson, Jonas
    Adolfsson, Jan
    Walsh, Patrick C
    Trent, Jeffrey M
    Duggan, David
    Carpten, John
    Grönberg, Henrik
    Isaacs, William B
    Inherited genetic variant predisposes to aggressive but not indolent prostate cancer.2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 5, p. 2136-2140Article in journal (Refereed)
    Abstract [en]

    Autopsy studies suggest that most aging men will develop lesions that, if detected clinically, would be diagnosed as prostate cancer (PCa). Most of these cancers are indolent and remain localized; however, a subset of PCa is aggressive and accounts for more than 27,000 deaths in the United States annually. Identification of factors specifically associated with risk for more aggressive PCa is urgently needed to reduce overdiagnosis and overtreatment of this common disease. To search for such factors, we compared the frequencies of SNPs among PCa patients who were defined as having either more aggressive or less aggressive disease in four populations examined in the Genetic Markers of Susceptibility (CGEMS) study performed by the National Cancer Institute. SNPs showing possible associations with disease severity were further evaluated in an additional three independent study populations from the United States and Sweden. In total, we studied 4,829 and 12,205 patients with more and less aggressive disease, respectively. We found that the frequency of the TT genotype of SNP rs4054823 at 17p12 was consistently higher among patients with more aggressive compared with less aggressive disease in each of the seven populations studied, with an overall P value of 2.1 x 10(-8) under a recessive model, exceeding the conservative genome-wide significance level. The difference in frequency was largest between patients with high-grade, non-organ-confined disease compared with those with low-grade, organ-confined disease. This study demonstrates that inherited variants predisposing to aggressive but not indolent PCa exist in the genome, and suggests that the clinical potential of such variants as potential early markers for risk of aggressive PCa should be evaluated.

  • 165.
    Zetterström, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Stewart, Heather G
    Bergemalm, Daniel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Jonsson, P Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Oliveberg, Mikael
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 35, p. 14157-14162Article in journal (Refereed)
    Abstract [en]

    Mutants of superoxide dismutase-1 (SOD1) cause ALS by an unidentified cytotoxic mechanism. We have previously shown that the stable SOD1 mutants D90A and G93A are abundant and show the highest levels in liver and kidney in transgenic murine ALS models, whereas the unstable G85R and G127X mutants are scarce but enriched in the CNS. These data indicated that minute amounts of misfolded SOD1 enriched in the motor areas might exert the ALS-causing cytotoxicity. A hydrophobic interaction chromatography (HIC) protocol was developed with the aim to determine the abundance of soluble misfolded SOD1 in tissues in vivo. Most G85R and G127X mutant SOD1s bound in the assay, but only minute subfractions of the D90A and G93A mutants. The absolute levels of HIC-binding SOD1 were, however, similar and broadly inversely related to lifespans in the models. They were generally enriched in the susceptible spinal cord. The HIC-binding SOD1 was composed of disulfide-reduced subunits lacking metal ions and also subunits that apparently carried nonnative intrasubunit disulfide bonds. The levels were high from birth until death and were comparable to the amounts of SOD1 that become sequestered in aggregates in the terminal stage. The HIC-binding SOD1 species ranged from monomeric to trimeric in size. These species form a least common denominator amongst SOD1 mutants with widely different molecular characteristics and might be involved in the cytotoxicity that causes ALS.

  • 166.
    Zettervall, Carl-Johan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Anderl, Ines
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Williams, Michael
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Palmer, Ruth
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    Kurucz, Eva
    Ando, Istvan
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
    A directed screen for genes involved in Drosophila blood cell activation2004In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 101, no 39, p. 14192-14197Article in journal (Refereed)
    Abstract [en]

    An attack by a parasitic wasp activates a vigorous cellular immune response in Drosophila larvae. This response is manifested by an increased number of circulating cells, the hemocytes, and by the appearance of a specialized class of hemocyte, the lamellocytes, which participate in the encapsulation and killing of the parasite. To study the molecular mechanisms of this response, we have overexpressed different genes in the hemocytes, by using the GAL4-upstream activating sequence system and a hemocyte-specific Hemese-GAL4 driver. Multiple transgenes were tested, representing several important signaling pathways. We found that the proliferation response and the activation of lamellocyte formation are independent phenomena. A drastic increase in the number of circulating hemocytes is caused by receptor tyrosine kinases, such as Egfr, Pvr, and Alk, as well as by the downstream signaling components Ras85D and pointed, supporting the notion that the Ras-mitogen-activated protein kinase pathway regulates hemocyte numbers. In the case of Pvr and Alk, this phenotype also is accompanied by lamellocyte formation. By contrast, constitutively active hopscotch and hemipterous give massive activation of lamellocyte formation with little or no increase in total hemocyte numbers. This finding indicates that both the Jak/Stat and the Jun kinase pathways affect lamellocyte formation. Still other signals, mediated by aop(ACT), Toll(10b), and Rac1 expression, cause a simultaneous increase in lamellocyte and total cell numbers, and the same effect is seen when WNT signaling is suppressed. We conclude that the activation of a cellular response is complex and affected by multiple signaling pathways.

  • 167. Zou, Yonggang
    et al.
    Liu, Bingbing
    Wang, Liancheng
    Liu, Dedi
    Yu, Shidan
    Wang, Peng
    Wang, Tianyi
    Yao, Mingguang
    Li, Quanjun
    Zou, Bo
    Cui, Tian
    Zou, Guangtian
    Wågberg, Thomas
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Sundqvist, Bertil
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Mao, Ho-Kwang
    Rotational dynamics of confined C60 from near-infrared Raman studies under high pressure2009In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 52, p. 22135-22138Article in journal (Refereed)
    Abstract [en]

    Peapods present a model system for studying the properties of dimensionally constrained crystal structures, whose dynamical properties are very important. We have recently studied the rotational dynamics of C60 molecules confined inside single walled carbon nanotube (SWNT) by analyzing the intermediate frequency mode lattice vibrations using near-infrared Raman spectroscopy. The rotation of C60 was tuned to a known state by applying high pressure, at which condition C60 first forms dimers at low pressure and then forms a single-chain, nonrotating, polymer structure at high pressure. In the latter state the molecules form chains with a 2-fold symmetry. We propose that the C60 molecules in SWNT exhibit an unusual type of ratcheted rotation due to the interaction between C60 and SWNT in the “hexagon orientation,” and the characteristic vibrations of ratcheted rotation becomes more obvious with decreasing temperature.

  • 168. Åstot, C
    et al.
    Dolezal, K
    Nordström, A
    Wang, Q
    Kunkel, T
    Moritz, T
    Chua, N H
    Sandberg, G
    An alternative cytokinin biosynthesis pathway2000In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 97, no 26, p. 14778-14783Article in journal (Refereed)
    Abstract [en]

    Studies of de novo cytokinin biosynthesis in isopentenyltransferase (ipt)-transformed Arabidopsis thaliana, involving in vivo deuterium labeling and mass spectrometry, showed that the biosynthetic rate of zeatinriboside-5'-monophosphate was around 66-fold higher than that of isopentenyladenosine-5'-monophosphate (iPMP), the proposed primary product of the Agrobacterium ipt. Double tracer analysis, using [(2)H(6)] isopentenyladenosine and deuterium oxide, provided evidence for an alternative, iPMP-independent, biosynthetic pathway for zeatin-type cytokinins, present in both ipt-expressing and wild-type Arabidopsis thaliana. Reduction of the biosynthetic flux in the alternative pathway by use of mevastatin, an inhibitor for 3-hydroxy-3-methylglutaryl CoA reductase, indicated a terpenoid origin for the side-chain precursor of the iPMP independent pathway.

  • 169.
    Överby, Anna K
    et al.
    Ludwig Institute for Cancer Research, Stockholm Branch, Karolinska Institute, P.O. Box 240, S-17177 Stockholm, Sweden.
    Pettersson, R F
    Grünewald, K
    Huiskonen, J T
    Insights into bunyavirus architecture from electron cryotomography of Uukuniemi virus2008In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, no 7, p. 2375-2379Article in journal (Refereed)
    Abstract [en]

    Bunyaviridae is a large family of viruses that have gained attention as "emerging viruses" because many members cause serious disease in humans, with an increasing number of outbreaks. These negative-strand RNA viruses possess a membrane envelope covered by glycoproteins. The virions are pleiomorphic and thus have not been amenable to structural characterization using common techniques that involve averaging of electron microscopic images. Here, we determined the three-dimensional structure of a member of the Bunyaviridae family by using electron cryotomography. The genome, incorporated as a complex with the nucleoprotein inside the virions, was seen as a thread-like structure partially interacting with the viral membrane. Although no ordered nucleocapsid was observed, lateral interactions between the two membrane glycoproteins determine the structure of the viral particles. In the most regular particles, the glycoprotein protrusions, or "spikes," were seen to be arranged on an icosahedral lattice, with T = 12 triangulation. This arrangement has not yet been proven for a virus. Two distinctly different spike conformations were observed, which were shown to depend on pH. This finding is reminiscent of the fusion proteins of alpha-, flavi-, and influenza viruses, in which conformational changes occur in the low pH of the endosome to facilitate fusion of the viral and host membrane during viral entry.

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