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  • 1.
    Billker, Oliver
    et al.
    Department of Biological Sciences Imperial College London London SW7 2AZ, United Kingdom.
    Dechamps, Sandrine
    Tewari, Rita
    Wenig, Gerald
    Franke-Fayard, Blandine
    Brinkmann, Volker
    Calcium and a calcium-dependent protein kinase regulate gamete formation and mosquito transmission in a malaria parasite2004In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 117, no 4, p. 503-514Article in journal (Refereed)
    Abstract [en]

    Transmission of malaria parasites to mosquitoes is initiated by the obligatory sexual reproduction of the parasite within the mosquito bloodmeal. Differentiation of specialized transmission stages, the gametocytes, into male and female gametes is induced by a small mosquito molecule, xanthurenic acid (XA). Using a Plasmodium berghei strain expressing a bioluminescent calcium sensor, we show that XA triggers a rapid rise in cytosolic calcium specifically in gametocytes that is essential for their differentiation into gametes. A member of a family of plant-like calcium dependent protein kinases, CDPK4, is identified as the molecular switch that translates the XA-induced calcium signal into a cellular response by regulating cell cycle progression in the male gametocyte. CDPK4 is shown to be essential for the sexual reproduction and mosquito transmission of P. berghei. This study reveals an unexpected function for a plant-like signaling pathway in cell cycle regulation and life cycle progression of a malaria parasite.

  • 2. Boj, Sylvia F
    et al.
    Hwang, Chang-Il
    Baker, Lindsey A
    Chio, Iok In Christine
    Engle, Dannielle D
    Corbo, Vincenzo
    Jager, Myrthe
    Ponz-Sarvise, Mariano
    Tiriac, Hervé
    Spector, Mona S
    Gracanin, Ana
    Oni, Tobiloba
    Yu, Kenneth H
    van Boxtel, Ruben
    Huch, Meritxell
    Rivera, Keith D
    Wilson, John P
    Feigin, Michael E
    Öhlund, Daniel
    Handly-Santana, Abram
    Ardito-Abraham, Christine M
    Ludwig, Michael
    Elyada, Ela
    Alagesan, Brinda
    Biffi, Giulia
    Yordanov, Georgi N
    Delcuze, Bethany
    Creighton, Brianna
    Wright, Kevin
    Park, Youngkyu
    Morsink, Folkert HM
    Molenaar, I Quintus
    Borel Rinkes, Inne H
    Cuppen, Edwin
    Hao, Yuan
    Jin, Ying
    Nijman, Isaac J
    Iacobuzio-Donahue, Christine
    Leach, Steven D
    Pappin, Darryl J
    Hammell, Molly
    Klimstra, David S
    Basturk, Olca
    Hruban, Ralph H
    Offerhaus, George Johan
    Vries, Robert GJ
    Clevers, Hans
    Tuveson, David A
    Organoid models of human and mouse ductal pancreatic cancer2015In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 160, no 1-2, p. 324-338Article in journal (Refereed)
    Abstract [en]

    Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.

  • 3. Bushell, Ellen
    et al.
    Gomes, Ana Rita
    Sanderson, Theo
    Anar, Burcu
    Girling, Gareth
    Herd, Colin
    Metcalf, Tom
    Modrzynska, Katarzyna
    Schwach, Frank
    Martin, Rowena E.
    Mather, Michael W.
    McFadden, Geoffrey I.
    Parts, Leopold
    Rutledge, Gavin G.
    Vaidya, Akhil B.
    Wengelnik, Kai
    Rayner, Julian C.
    Billker, Oliver
    Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK.
    Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes2017In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 170, no 2, p. 260-272.e1-e4Article in journal (Refereed)
    Abstract [en]

    The genomes of malaria parasites contain many genes of unknown function. To assist drug development through the identification of essential genes and pathways, we have measured competitive growth rates in mice of 2,578 barcoded Plasmodium berghei knockout mutants, representing >50% of the genome, and created a phenotype database. At a single stage of its complex life cycle, P. berghei requires two-thirds of genes for optimal growth, the highest proportion reported from any organism and a probable consequence of functional optimization necessitated by genomic reductions during the evolution of parasitism. In contrast, extreme functional redundancy has evolved among expanded gene families operating at the parasite-host interface. The level of genetic redundancy in a single-celled organism may thus reflect the degree of environmental variation it experiences. In the case of Plasmodium parasites, this helps rationalize both the relative successes of drugs and the greater difficulty of making an effective vaccine.

  • 4.
    Chabes, Andrei
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Georgieva, Bilyana
    Domkin, Vladimir
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Zhao, Xiaolan
    Rothstein, Rodney
    Thelander, Lars
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Survival of DNA damage in yeast directly depends on increased dNTP levels allowed by relaxed feedback inhibition of ribonucleotide reductase.2003In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 112, no 3, p. 391-401Article in journal (Refereed)
    Abstract [en]

    In eukaryotes, DNA damage elicits a multifaceted response that includes cell cycle arrest, transcriptional activation of DNA repair genes, and, in multicellular organisms, apoptosis. We demonstrate that in Saccharomyces cerevisiae, DNA damage leads to a 6- to 8-fold increase in dNTP levels. This increase is conferred by an unusual, relaxed dATP feedback inhibition of ribonucleotide reductase (RNR). Complete elimination of dATP feedback inhibition by mutation of the allosteric activity site in RNR results in 1.6-2 times higher dNTP pools under normal growth conditions, and the pools increase an additional 11- to 17-fold during DNA damage. The increase in dNTP pools dramatically improves survival following DNA damage, but at the same time leads to higher mutation rates. We propose that increased survival and mutation rates result from more efficient translesion DNA synthesis at elevated dNTP concentrations.

  • 5. Chio, Iok In Christine
    et al.
    Jafarnejad, Seyed Mehdi
    Ponz-Sarvise, Mariano
    Park, Youngkyu
    Rivera, Keith
    Palm, Wilhelm
    Wilson, John
    Sangar, Vineet
    Hao, Yuan
    Öhlund, Daniel
    Cold Spring Harbor Laboratory.
    Wright, Kevin
    Filippini, Dea
    Lee, Eun Jung
    Da Silva, Brandon
    Schoepfer, Christina
    Wilkinson, John Erby
    Buscaglia, Jonathan M
    DeNicola, Gina M
    Tiriac, Herve
    Hammell, Molly
    Crawford, Howard C
    Schmidt, Edward E
    Thompson, Craig B
    Pappin, Darryl J
    Sonenberg, Nahum
    Tuveson, David A
    NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer2016In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 166, no 4, p. 936-976Article in journal (Refereed)
    Abstract [en]

    Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.

  • 6. Cruz-Ramírez, Alfredo
    et al.
    Díaz-Triviño, Sara
    Blilou, Ikram
    Grieneisen, Verônica A.
    Sozzani, Rosangela
    Zamioudis, Christos
    Miskolczi, Pál
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Department of Forest Genetics and Plant Physiology, Umeå Plant Science Center, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Nieuwland, Jeroen
    Benjamins, René
    Dhonukshe, Pankaj
    Caballero-Pérez, Juan
    Horvath, Beatrix
    Long, Yuchen
    Mähönen, Ari Pekka
    Zhang, Hongtao
    Xu, Jian
    Murray, James A. H.
    Benfey, Philip N.
    Bako, Laszlo
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Department of Forest Genetics and Plant Physiology, Umeå Plant Science Center, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Marée, Athanasius F. M.
    Scheres, Ben
    A Bistable Circuit Involving SCARECROW-RETINOBLASTOMA Integrates Cues to Inform Asymmetric Stem Cell Division2012In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 150, no 5, p. 1002-1015Article in journal (Refereed)
    Abstract [en]

    In plants, where cells cannot migrate, asymmetric cell divisions (ACDs) must be confined to the appropriate spatial context. We investigate tissue-generating asymmetric divisions in a stem cell daughter within the Arabidopsis root. Spatial restriction of these divisions requires physical binding of the stem cell regulator SCARECROW (SCR) by the RETINOBLASTOM-RELATED (RBR) protein. In the stem cell niche, SCR activity is counteracted by phosphorylation of RBR through a cyclinD6;1-CDK complex. This cyclin is itself under transcriptional control of SCR and its partner SHORT ROOT (SHR), creating a robust bistable circuit with either high or low SHR-SCR complex activity. Auxin biases this circuit by promoting CYCD6;1 transcription. Mathematical modeling shows that ACDs are only switched on after integration of radial and longitudinal information, determined by SHR and auxin distribution, respectively. Coupling of cell-cycle progression to protein degradation resets the circuit, resulting in a "flip flop" that constrains asymmetric cell division to the stem cell region.

  • 7. Gardai, Shyra J
    et al.
    McPhillips, Kathleen A
    Frasch, S Courtney
    Janssen, William J
    Starefeldt, Anna
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Murphy-Ullrich, Joanne E
    Bratton, Donna L
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Michalak, Marek
    Henson, Peter M
    Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte2005In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 123, no 2, p. 321-334Article in journal (Refereed)
    Abstract [en]

    Apoptotic-cell removal is critical for development, tissue homeostasis, and resolution of inflammation. Although many candidate systems exist, only phosphatidylserine has been identified as a general recognition ligand on apoptotic cells. We demonstrate here that calreticulin acts as a second general recognition ligand by binding and activating LDL-receptor-related protein (LRP) on the engulfing cell. Since surface calreticulin is also found on viable cells, a mechanism preventing inadvertent uptake was sought. Disruption of interactions between CD47 (integrin-associated protein) on the target cell and SIRPalpha (SHPS-1), a heavily glycosylated transmembrane protein on the engulfing cell, permitted uptake of viable cells in a calreticulin/LRP-dependent manner. On apoptotic cells, CD47 was altered and/or lost and no longer activated SIRPalpha. These changes on the apoptotic cell create an environment where "don't eat me" signals are rendered inactive and "eat me" signals, including calreticulin and phosphatidylserine, congregate together and signal for removal.

  • 8. Gardino, Alexandra K
    et al.
    Villali, Janice
    Kivenson, Aleksandr
    Lei, Ming
    Liu, Ce Feng
    Steindel, Phillip
    Eisenmesser, Elan Z
    Labeikovsky, Wladimir
    Wolf-Watz, Magnus
    Umeå University, Faculty of Science and Technology, Chemistry.
    Clarkson, Michael W
    Kern, Dorothee
    Transient Non-native Hydrogen Bonds Promote Activation of a Signaling Protein2009In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 139, no 6, p. 1109-18Article in journal (Refereed)
    Abstract [en]

    SummaryPhosphorylation is a common mechanism for activating proteins within signaling pathways. Yet, the molecular transitions between the inactive and active conformational states are poorly understood. Here we quantitatively characterize the free-energy landscape of activation of a signaling protein, nitrogen regulatory protein C (NtrC), by connecting functional protein dynamics of phosphorylation-dependent activation to protein folding and show that only a rarely populated, pre-existing active conformation is energetically stabilized by phosphorylation. Using nuclear magnetic resonance (NMR) dynamics, we test an atomic scale pathway for the complex conformational transition, inferred from molecular dynamics simulations (Lei et al., 2009). The data show that the loss of native stabilizing contacts during activation is compensated by non-native transient atomic interactions during the transition. The results unravel atomistic details of native-state protein energy landscapes by expanding the knowledge about ground states to transition landscapes.

  • 9. Hille, Frank
    et al.
    Richter, Hagen
    Wong, Shi Pey
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Regulation in Infection Biology, Max Planck Institute for Infection Biology, Berlin, Germany; Institute for Biology, Humboldt University, Germany.
    Bratovic, Majda
    Ressel, Sarah
    Charpentier, Emmanuelle
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Regulation in Infection Biology, Max Planck Institute for Infection Biology, Berlin, Germany; Institute for Biology, Humboldt University, Germany.
    The Biology of CRISPR-Cas: Backward and Forward2018In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 172, no 6, p. 1239-1259Article, review/survey (Refereed)
    Abstract [en]

    In bacteria and archaea, clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins constitute an adaptive immune system against phages and other foreign genetic elements. Here, we review the biology of the diverse CRISPR-Cas systems and the major progress achieved in recent years in understanding the underlying mechanisms of the three stages of CRISPR-Cas immunity: adaptation, crRNA biogenesis, and interference. The ecology and regulation of CRISPR-Cas in the context of phage infection, the roles of these systems beyond immunity, and the open questions that propel the field forward are also discussed.

  • 10. Kim, Y J
    et al.
    Björklund, Stefan
    Li, Y
    Sayre, M H
    Kornberg, R D
    A multiprotein mediator of transcriptional activation and its interaction with the C-terminal repeat domain of RNA polymerase II.1994In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 77, no 4, p. 599-608Article in journal (Refereed)
    Abstract [en]

    A mediator was isolated from yeast that enabled a response to the activator proteins GAL4-VP16 and GCN4 in a transcription system reconstituted with essentially homogeneous basal factors and RNA polymerase II. The mediator comprised some 20 polypeptides, including the three subunits of TFIIF and other polypeptides cross-reactive with antisera against GAL11, SUG1, SRB2, SRB4, SRB5, and SRB6 proteins. Mediator not only enabled activated transcription but also conferred 8-fold greater activity in basal transcription and 12-fold greater efficiency of phosphorylation of RNA polymerase II by the TFIIH-associated C-terminal repeat domain (CTD) kinase, indicative of mediator-CTD interaction. A holoenzyme form of RNA polymerase II was independently isolated that supported a response to activator proteins with purified basal factors. The holoenzyme proved to consist of mediator associated with core 12-subunit RNA polymerase II.

  • 11.
    Loh, Edmund
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Dussurget, Olivier
    Pasteur Institute, France.
    Gripenland, Jonas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Vaitkevicius, Karolis
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Tiensuu, Teresa
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Mandin, Pierre
    Pasteur Institute, France.
    Repoila, Francis
    Pasteur Institute, France.
    Buchrieser, Carmen
    Pasteur Institute, France.
    Cossart, Pascale
    Pasteur Institute, France.
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    A trans-acting riboswitch controls expression of the virulence regulator PrfA in Listeria monocytogenes2009In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 139, no 4, p. 770-779Article in journal (Refereed)
    Abstract [en]

    Riboswitches are RNA elements acting in cis, controlling expression of their downstream genes through a metabolite-induced alteration of their secondary structure. Here, we demonstrate that two S-adenosylmethionine (SAM) riboswitches, SreA and SreB, can also function in trans and act as noncoding RNAs in Listeria monocytogenes. SreA and SreB control expression of the virulence regulator PrfA by binding to the 5´-untranslated region of its mRNA. Absence of the SAM riboswitches SreA and SreB increases the level of PrfA and virulence gene expression in L. monocytogenes. Thus, the impact of the SAM riboswitches on PrfA expression highlights a link between bacterial virulence and nutrient availability. Together, our results uncover an unexpected role for riboswitches and a distinct class of regulatory noncoding RNAs in bacteria.

  • 12.
    Neely, G Gregory
    et al.
    Austrian Academy of Science.
    Hess, Andreas
    University of Erlangen Nurnberg.
    Costigan, Michael
    Harvard University.
    Keene, Alex C
    NYU.
    Goulas, Spyros
    Austrian Academy of Science.
    Langeslag, Michiel
    Innsbruck Medical University.
    Griffin, Robert S
    Massachusetts General Hospital.
    Belfer, Inna
    University of Pittsburgh.
    Dai, Feng
    University of Pittsburgh.
    Smith, Shad B
    University N Carolina.
    Diatchenko, Luda
    University N Carolina.
    Gupta, Vaijayanti
    Strand Life Science Pvt Ltd.
    Xia, Cui-Ping
    Austrian Academy Science.
    Amann, Sabina
    Austrian Academy of Science.
    Kreitz, Silke
    University of Erlangen Nurnberg.
    Heindl-Erdmann, Cornelia
    University of Erlangen Nurnberg.
    Wolz, Susanne
    University of Erlangen Nurnberg.
    Ly, Cindy V
    Strand Life Science Pvt Ltd.
    Sarangi, Rinku
    Strand Life Science Pvt Ltd.
    Dan, Debasis
    Strand Life Science Pvt Ltd.
    Novatchkova, Maria
    Austrian Academy of Science.
    Rosenzweig, Mark
    Brandeis University.
    Gibson, Dustin G
    University N Carolina.
    Truong, Darwin
    Austrian Academy of Science.
    Schramek, Daniel
    Austrian Academy of Science.
    Zoranovic, Tamara
    Austrian Academy of Science.
    Cronin, Shane J F
    Austrian Academy of Science.
    Angjeli, Belinda
    Austrian Academy of Science.
    Brune, Kay
    University of Erlangen Nurnberg.
    Dietzl, Georg
    Stanford University.
    Maixner, William
    University N Carolina.
    Meixner, Arabella
    Austrian Academy of Science.
    Thomas, Winston
    Deltagen Inc.
    Pospisilik, J Andrew
    Max Planck Institute.
    Alenius, Mattias
    Linköpings universitet, Hälsouniversitetet.
    Kress, Michaela
    Innsbruck Medical University.
    Subramaniam, Sai
    Strand Life Science Pvt Ltd.
    Garrity, Paul A
    Brandeis University.
    Bellen, Hugo J
    Baylor College of Medicine.
    Woolf, Clifford J
    Harvard University.
    Penninger, Josef M
    Austrian Academy of Science.
    A Genome-wide Drosophila Screen for Heat Nociception Identifies alpha 2 delta 3 as an Evolutionarily Conserved Pain Gene2010In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 143, no 4, p. 628-638Article in journal (Refereed)
    Abstract [en]

    Worldwide, acute, and chronic pain affects 20% of the adult population and represents an enormous financial and emotional burden. Using genome-wide neuronal-specific RNAi knockdown in Drosophila, we report a global screen for an innate behavior and identify hundreds of genes implicated in heat nociception, including the alpha 2 delta family calcium channel subunit straightjacket (stj). Mice mutant for the stj ortholog CACNA2D3 (alpha 2 delta 3) also exhibit impaired behavioral heat pain sensitivity. In addition, in humans, alpha 2 delta 3 SNP variants associate with reduced sensitivity to acute noxious heat and chronic back pain. Functional imaging in alpha 2 delta 3 mutant mice revealed impaired transmission of thermal pain-evoked signals from the thalamus to higher-order pain centers. Intriguingly, in alpha 2 delta 3 mutant mice, thermal pain and tactile stimulation triggered strong cross-activation, or synesthesia, of brain regions involved in vision, olfaction, and hearing.

  • 13.
    Pietra, Stefano
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Grebe, Markus
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Auxin paves the way for planar morphogenesis2010In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 143, no 1, p. 29-31Article in journal (Refereed)
  • 14. Saitoh, Shigeaki
    et al.
    Chabes, Andrei
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    McDonald, W Hayes
    Thelander, Lars
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Yates, John R
    Russell, Paul
    Cid13 is a cytoplasmic poly(A) polymerase that regulates ribonucleotide reductase mRNA.2002In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 109, no 5, p. 563-73Article in journal (Refereed)
    Abstract [en]

    Fission yeast Cid13 and budding yeast Trf4/5 are members of a newly identified nucleotidyltransferase family conserved from yeast to man. Trf4/5 are thought to be essential DNA polymerases. We report that Cid13 is a poly(A) polymerase. Unlike conventional poly(A) polymerases, which act in the nucleus and indiscriminately polyadenylate all mRNA, Cid13 is a cytoplasmic enzyme that specifically targets suc22 mRNA that encodes a subunit of ribonucleotide reductase (RNR). cid13 mutants have reduced dNTP pools and are sensitive to hydroxyurea, an RNR inhibitor. We propose that Cid13 defines a cytoplasmic form of poly(A) polymerase important for DNA replication and genome maintenance.

  • 15.
    Sandblad, Linda
    et al.
    Structural and Computational Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
    Busch, Karl Emanuel
    Tittmann, Peter
    Gross, Heinz
    Brunner, Damian
    Hoenger, Andreas
    The Schizosaccharomyces pombe EB1 homolog Mal3p binds and stabilizes the microtubule lattice seam2006In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 127, no 7, p. 1415-1424Article in journal (Refereed)
    Abstract [en]

    End binding 1 (EB1) proteins are highly conserved regulators of microtubule dynamics. Using electron microscopy (EM) and high-resolution surface shadowing we have studied the microtubule-binding properties of the fission yeast EB1 homolog Mal3p. This allowed for a direct visualization of Mal3p bound on the surface of microtubules. Mal3p particles usually formed a single line on each microtubule along just one of the multiple grooves that are formed by adjacent protofilaments. We provide structural data showing that the alignment of Mal3p molecules coincides with the microtubule lattice seam as well as data suggesting that Mal3p not only binds but also stabilizes this seam. Accordingly, Mal3p stabilizes microtubules through a specific interaction with what is potentially the weakest part of the microtubule in a way not previously demonstrated. Our findings further suggest that microtubules exhibit two distinct reaction platforms on their surface that can independently interact with target structures such as microtubule-associated proteins, motors, kinetochores, or membranes.

  • 16. Stanway, Rebecca R.
    et al.
    Bushell, Ellen
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Chiappino-Pepe, Anush
    Roques, Magali
    Sanderson, Theo
    Franke-Fayard, Blandine
    Caldelari, Reto
    Golomingi, Murielle
    Nyonda, Mary
    Pandey, Vikash
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Laboratory of Computational Systems Biotechnology, École Polytechnique Fédérale de Lausanne, EPFL, Lausanne 1015, Switzerland.
    Schwach, Frank
    Chevalley, Séverine
    Ramesar, Jai
    Metcalf, Tom
    Herd, Colin
    Burda, Paul-Christian
    Rayner, Julian C.
    Soldati-Favre, Dominique
    Janse, Chris J.
    Hatzimanikatis, Vassily
    Billker, Oliver
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
    Heussler, Volker T.
    Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage2019In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 179, no 5, p. 1112-1128.e1-e15Article in journal (Refereed)
    Abstract [en]

    Plasmodium gene functions in mosquito and liver stages remain poorly characterized due to limitations in the throughput of phenotyping at these stages. To fill this gap, we followed more than 1,300 barcoded P. berghei mutants through the life cycle. We discover 461 genes required for efficient parasite transmission to mosquitoes through the liver stage and back into the bloodstream of mice. We analyze the screen in the context of genomic, transcriptomic, and metabolomic data by building a thermodynamic model of P. berghei liver-stage metabolism, which shows a major reprogramming of parasite metabolism to achieve rapid growth in the liver. We identify seven metabolic subsystems that become essential at the liver stages compared with asexual blood stages: type II fatty acid synthesis and elongation (FAE), tricarboxylic acid, amino sugar, heme, lipoate, and shikimate metabolism. Selected predictions from the model are individually validated in single mutants to provide future targets for drug development.

  • 17. Tao, Yi
    et al.
    Ferrer, Jean-Luc
    Ljung, Karin
    Pojer, Florence
    Hong, Fangxin
    Long, Jeff A
    Li, Lin
    Moreno, Javier E
    Bowman, Marianne E
    Ivans, Lauren J
    Cheng, Youfa
    Lim, Jason
    Zhao, Yunde
    Ballaré, Carlos L
    Sandberg, Göran
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Noel, Joseph P
    Chory, Joanne
    Rapid synthesis of auxin via a new tryptophan-dependent pathway is required for shade avoidance in plants2008In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 133, no 1, p. 164-176Article in journal (Refereed)
    Abstract [en]

    Plants grown at high densities perceive a decrease in the red to far-red (R:FR) ratio of incoming light, resulting from absorption of red light by canopy leaves and reflection of far-red light from neighboring plants. These changes in light quality trigger a series of responses known collectively as the shade avoidance syndrome. During shade avoidance, stems elongate at the expense of leaf and storage organ expansion, branching is inhibited, and flowering is accelerated. We identified several loci in Arabidopsis, mutations in which lead to plants defective in multiple shade avoidance responses. Here we describe TAA1, an aminotransferase, and show that TAA1 catalyzes the formation of indole-3-pyruvic acid (IPA) from L-tryptophan (L-Trp), the first step in a previously proposed, but uncharacterized, auxin biosynthetic pathway. This pathway is rapidly deployed to synthesize auxin at the high levels required to initiate the multiple changes in body plan associated with shade avoidance.

  • 18.
    Åström, Stefan U
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Byström, Anders S
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rit1, a tRNA backbone-modifying enzyme that mediates initiator and elongator tRNA discrimination1994In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 79, no 3, p. 535-546Article in journal (Refereed)
    Abstract [en]

    Using a genetic screen in yeast aimed at identifying cellular factors involved in initiator and elongator methionine tRNA discrimination in the translational process, we have identified a mutation that abolish the requirement for elongator methionine tRNA. The gene affected, which we call the ribosylation of the initiator tRNA gene or RIT1, encodes a 2'-O-ribosyl phosphate transferase. This enzyme modifies exclusively the initiator tRNA in position 64 using 5'-phosphoribosyl-1'-pyrophosphate as the modification donor. As the initiator tRNA participates both in the initiation and elongation of translation in a rit1 strain, we conclude that the 2'-O-ribosyl phosphate modification discriminates the initiator tRNAs from the elongator tRNAs during protein synthesis. The modification enzyme was shown to recognize the stem-loop IV region that is unique in eukaryotic cytoplasmic initiator tRNAs.

  • 19.
    Öst, Anita
    et al.
    Linköpings universitet, Avdelningen för cellbiologi.
    Lempradl, Adelheid
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Casas, Eduard
    Institute Medical Predict and Personalitzada Canc, Spain; ICO Hospital GermansTrias and Pujol, Spain.
    Weigert, Melanie
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Tiko, Theodor
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Deniz, Merdin
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Pantano, Lorena
    Institute Medical Predict and Personalitzada Canc, Spain.
    Boenisch, Ulrike
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Itskov, Pavel M.
    Champalimaud Centre Unknown, Portugal.
    Stoeckius, Marlon
    Max Delbruck Centre Molecular Med, Germany.
    Ruf, Marius
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Rajewsky, Nikolaus
    Max Delbruck Centre Molecular Med, Germany.
    Reuter, Gunter
    University of Halle Wittenberg, Germany.
    Iovino, Nicola
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Ribeiro, Carlos
    Champalimaud Centre Unknown, Portugal.
    Alenius, Mattias
    Linköpings universitet, Avdelningen för cellbiologi.
    Heyne, Steffen
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Vavouri, Tanya
    Institute Medical Predict and Personalitzada Canc, Spain; ICO Hospital GermansTrias and Pujol, Spain.
    Pospisilik, J. Andrew
    Max Planck Institute Immunobiol and Epigenet, Germany.
    Paternal Diet Defines Offspring Chromatin State and Intergenerational Obesity2014In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 159, no 6, p. 1352-1364Article in journal (Refereed)
    Abstract [en]

    The global rise in obesity has revitalized a search for genetic and epigenetic factors underlying the disease. We present a Drosophila model of paternal-diet-induced intergenerational metabolic reprogramming (IGMR) and identify genes required for its encoding in offspring. Intriguingly, we find that as little as 2 days of dietary intervention in fathers elicits obesity in offspring. Paternal sugar acts as a physiological suppressor of variegation, desilencing chromatin-state-defined domains in both mature sperm and in offspring embryos. We identify requirements for H3K9/K27me3-dependent reprogramming of metabolic genes in two distinct germline and zygotic windows. Critically, we find evidence that a similar system may regulate obesity susceptibility and phenotype variation in mice and humans. The findings provide insight into the mechanisms underlying intergenerational metabolic reprogramming and carry profound implications for our understanding of phenotypic variation and evolution.

1 - 19 of 19
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