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  • 1. Arab, Khelifa
    et al.
    Park, Yoon Jung
    Lindroth, Anders M.
    Schaefer, Andrea
    Oakes, Christopher
    Weichenhan, Dieter
    Lukanova, Annekatrin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lundin, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Risch, Angela
    Meister, Michael
    Dienemann, Hendrik
    Dyckhoff, Gerhard
    Herold-Mende, Christel
    Grummt, Ingrid
    Niehrs, Christof
    Plass, Christoph
    Long Noncoding RNA TARID Directs Demethylation and Activation of the Tumor Suppressor TCF21 via GADD45A2014Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 55, nr 4, s. 604-614Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DNA methylation is a dynamic and reversible process that governs gene expression during development and disease. Several examples of active DNA demethylation have been documented, involving genome-wide and gene-specific DNA demethylation. How demethylating enzymes are targeted to specific genomic loci remains largely unknown. We show that an antisense lncRNA, termed TARID (for TCF21 antisense RNA inducing demethylation), activates TCF21 expression by inducing promoter demethylation. TARID interacts with both the TCF21 promoter and GADD45A (growth arrest and DNA-damage-inducible, alpha), a regulator of DNA demethylation. GADD45A in turn recruits thymine-DNA glycosylase for base excision repair-mediated demethylation involving oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in the TCF21 promoter by ten-eleven translocation methylcytosine dioxygenase proteins. The results reveal a function of lncRNAs, serving as a genomic address label for GADD45A-mediated demethylation of specific target genes.

  • 2. Boija, Ann
    et al.
    Mahat, Dig Bijay
    Zare, Aman
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Holmqvist, Per-Henrik
    Philip, Philge
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Meyers, David J
    Cole, Philip A
    Lis, John T
    Stenberg, Per
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Mannervik, Mattias
    CBP Regulates Recruitment and Release of Promoter-Proximal RNA Polymerase II2017Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 68, nr 3, s. 491-503.e5Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Transcription activation involves RNA polymerase II (Pol II) recruitment and release from the promoter into productive elongation, but how specific chromatin regulators control these steps is unclear. Here, we identify a novel activity of the histone acetyltransferase p300/CREB-binding protein (CBP) in regulating promoter-proximal paused Pol II. We find that Drosophila CBP inhibition results in "dribbling" of Pol II from the pause site to positions further downstream but impedes transcription through the +1 nucleosome genome-wide. Promoters strongly occupied by CBP and GAGA factor have high levels of paused Pol II, a unique chromatin signature, and are highly expressed regardless of cell type. Interestingly, CBP activity is rate limiting for Pol II recruitment to these highly paused promoters through an interaction with TFIIB but for transit into elongation by histone acetylation at other genes. Thus, CBP directly stimulates both Pol II recruitment and the ability to traverse the first nucleosome, thereby promoting transcription of most genes.

  • 3.
    Bäckström, Stefan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Elfving, Nils
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Nilsson, Robert
    Wingsle, Gunnar
    Björklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Purification of a plant mediator from Arabidopsis thaliana identifies PFT1 as the Med25 subunit2007Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 26, nr 5, s. 717-729Artikel i tidskrift (Refereegranskat)
  • 4. Dellino, Gaetano I
    et al.
    Schwartz, Yuri B
    University of Geneva, Switzerlandc.
    Farkas, Gabriella
    McCabe, Donna
    Elgin, Sarah C R
    Pirrotta, Vincenzo
    Polycomb silencing blocks transcription initiation.2004Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 13, nr 6, s. 887-93Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polycomb (PcG) complexes maintain the silent state of target genes. The mechanism of silencing is not known but has been inferred to involve chromatin packaging to block the access of transcription factors. We have studied the effect of PcG silencing on the hsp26 heat shock promoter. While silencing does decrease the accessibility of some restriction enzyme sites to some extent, it does not prevent the binding of TBP, RNA polymerase, or the heat shock factor to the hsp26 promoter, as shown by chromatin immunoprecipitation. However, we find that in the repressed state, the RNA polymerase cannot initiate transcription. We conclude that, rather than altering chromatin structure to block accessibility, PcG silencing in this construct targets directly the activity of the transcriptional machinery at the promoter.

  • 5.
    Esberg, Anders
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Huang, Bo
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Johansson, Marcus J O
    Byström, Anders
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Elevated levels of two tRNA species bypass the requirement for elongator complex in transcription and exocytosis.2006Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 24, nr 1, s. 139-148Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Saccharomyces cerevisiae Elongator complex consisting of the six Elp1-Elp6 proteins has been proposed to participate in three distinct cellular processes: transcriptional elongation, polarized exocytosis, and formation of modified wobble uridines in tRNA. Therefore it was important to clarify whether Elongator has three distinct functions or whether it regulates one key process that leads to multiple downstream effects. Here, we show that the phenotypes of Elongator-deficient cells linking the complex to transcription and exocytosis are suppressed by increased expression of two tRNA species. Elongator is required for formation of the mcm(5) group of the modified wobble nucleoside 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U) in these tRNAs. Hence, in cells with normal levels of these tRNAs, presence of mcm(5)s(2)U is crucial for posttranscriptional expression of gene products important in transcription and exocytosis. Our results indicate that the physiologically relevant function of the evolutionary-conserved Elongator complex is in formation of modified nucleosides in tRNAs.

  • 6. Evans, Margery L.
    et al.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Taylor, Jonathan D.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Götheson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Li, Fei
    Koch, Marion
    Sefer, Lea
    Matthews, Steve J.
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chapman, Matthew R.
    Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
    The Bacterial Curli System Possesses a Potent and Selective Inhibitor of Amyloid Formation2015Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 57, nr 3, s. 445-455Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Summary Curli are extracellular functional amyloids that are assembled by enteric bacteria during biofilm formation and host colonization. An efficient secretion system and chaperone network ensures that the major curli fiber subunit, CsgA, does not form intracellular amyloid aggregates. We discovered that the periplasmic protein CsgC was a highly effective inhibitor of CsgA amyloid formation. In the absence of CsgC, CsgA formed toxic intracellular aggregates. In vitro, CsgC inhibited CsgA amyloid formation at substoichiometric concentrations and maintained CsgA in a non-β-sheet-rich conformation. Interestingly, CsgC inhibited amyloid assembly of human α-synuclein, but not Aβ42, in vitro. We identified a common D-Q-Φ-X0,1-G-K-N-ζ-E motif in CsgC client proteins that is not found in Aβ42. CsgC is therefore both an efficient and selective amyloid inhibitor. Dedicated functional amyloid inhibitors may be a key feature that distinguishes functional amyloids from disease-associated amyloids.

  • 7. Forey, Romain
    et al.
    Poveda, Ana
    Sharma, Sushma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Barthe, Antoine
    Padioleau, Ismael
    Renard, Claire
    Lambert, Robin
    Skrzypczak, Magdalena
    Ginalski, Krzysztof
    Lengronne, Armelle
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Pardo, Benjamin
    Pasero, Philippe
    Mec1 Is Activated at the Onset of Normal S Phase by Low-dNTP Pools Impeding DNA Replication2020Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Mec1 and Rad53 kinases play a central role during acute replication stress in budding yeast. They are also essential for viability in normal growth conditions, but the signal that activates the Mec1-Rad53 pathway in the absence of exogenous insults is currently unknown. Here, we show that this pathway is active at the onset of normal S phase because deoxyribonucleotide triphosphate (dNTP) levels present in G1 phase may not be sufficient to support processive DNA synthesis and impede DNA replication. This activation can be suppressed experimentally by increasing dNTP levels in G1 phase. Moreover, we show that unchallenged cells entering S phase in the absence of Rad53 undergo irreversible fork collapse and mitotic catastrophe. Together, these data indicate that cells use suboptimal dNTP pools to detect the onset of DNA replication and activate the Mec1-Rad53 pathway, which in turn maintains functional forks and triggers dNTP synthesis, allowing the completion of DNA replication.

  • 8. Gan, Haiyun
    et al.
    Yu, Chuanhe
    Devbhandari, Sujan
    Sharma, Sushma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Han, Junhong
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Remus, Dirk
    Zhang, Zhiguo
    Checkpoint Kinase Rad53 Couples Leading- and Lagging-Strand DNA Synthesis under Replication Stress2017Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 68, nr 2, s. 446-455Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The checkpoint kinase Rad53 is activated during replication stress to prevent fork collapse, an essential but poorly understood process. Here we show that Rad53 couples leading- and lagging-strand synthesis under replication stress. In rad53-1 cells stressed by dNTP depletion, the replicative DNA helicase, MCM, and the leading-strand DNA polymerase, Pol ε, move beyond the site of DNA synthesis, likely unwinding template DNA. Remarkably, DNA synthesis progresses further along the lagging strand than the leading strand, resulting in the exposure of long stretches of single-stranded leading-strand template. The asymmetric DNA synthesis in rad53-1 cells is suppressed by elevated levels of dNTPs in vivo, and the activity of Pol ε is compromised more than lagging-strand polymerase Pol δ at low dNTP concentrations in vitro. Therefore, we propose that Rad53 prevents the generation of excessive ssDNA under replication stress by coordinating DNA unwinding with synthesis of both strands.

  • 9.
    Ganai, Rais Ahmad
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Howard Hughes Medical Institute, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, NY 10016, USA.
    Johansson, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    DNA Replication - A Matter of Fidelity2016Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 62, nr 5, s. 745-755Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The fidelity of DNA replication is determined by many factors, here simplified as the contribution of the DNA polymerase (nucleotide selectivity and proofreading), mismatch repair, a balanced supply of nucleotides, and the condition of the DNA template (both in terms of sequence context and the presence of DNA lesions). This review discusses the contribution and interplay between these factors to the overall fidelity of DNA replication.

  • 10. Heckl, Dirk
    et al.
    Charpentier, Emmanuelle
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Department of Regulation in Infection Biology, Helmholtz Centre for Infection Research, Germany ; Department of Regulation in Infection Biology, Hannover Medical School, Hannover, Germany.
    Toward whole-transcriptome editing with CRISPR-Cas92015Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 58, nr 4, s. 560-562Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Targeted regulation of gene expression holds huge promise for biomedical research. In a series of recent publications (Gilbert et al., 2014; Konermann et al., 2015; Zalatan et al., 2015), sophisticated, multiplex-compatible transcriptional activator systems based on the CRISPR-Cas9 technology and genome-scale libraries advance the field toward whole-transcriptome control.

  • 11. Meydan, Sezen
    et al.
    Marks, James
    Klepacki, Dorota
    Sharma, Virag
    Baranov, Pavel V.
    Firth, Andrew E.
    Margus, Tonu
    Center for Biomolecular Sciences-m/c 870, University of Illinois at Chicago, 900 S. Ashland Ave., Chicago, IL 60607, USA.
    Kefi, Amira
    Vazquez-Laslop, Nora
    Mankin, Alexander S.
    Retapamulin-Assisted Ribosome Profiling Reveals the Alternative Bacterial Proteome2019Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 74, nr 3, s. 481-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The use of alternative translation initiation sites enables production of more than one protein from a single gene, thereby expanding the cellular proteome. Although several such examples have been serendipitously found in bacteria, genome-wide mapping of alternative translation start sites has been unattainable. We found that the antibiotic retapamulin specifically arrests initiating ribosomes at start codons of the genes. Retapamulin-enhanced Ribo-seq analysis (Ribo-RET) not only allowed mapping of conventional initiation sites at the beginning of the genes, but strikingly, it also revealed putative internal start sites in a number of Escherichia coli genes. Experiments demonstrated that the internal start codons can be recognized by the ribosomes and direct translation initiation in vitro and in vivo. Proteins, whose synthesis is initiated at internal in-frame and out-of-frame start sites, can be functionally important and contribute to the "alternative" bacterial proteome. The internal start sites may also play regulatory roles in gene expression.

  • 12. Minina, Elena A.
    et al.
    Staal, Jens
    Alvarez, Vanina E.
    Berges, John A.
    Berman-Frank, Ilana
    Beyaert, Rudi
    Bidle, Kay D.
    Bornancin, Frederic
    Casanova, Magali
    Cazzulo, Juan J.
    Choi, Chang Jae
    Coll, Nuria S.
    Dixit, Vishva M.
    Dolinar, Marko
    Fasel, Nicolas
    Funk, Christiane
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Gallois, Patrick
    Gevaert, Kris
    Gutierrez-Beltran, Emilio
    Hailfinger, Stephan
    Klemencic, Marina
    Koonin, Eugene V.
    Krappmann, Daniel
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Machado, Mauricio F. M.
    Madeo, Frank
    Megeney, Lynn A.
    Moschou, Panagiotis N.
    Mottram, Jeremy C.
    Nystrom, Thomas
    Osiewacz, Heinz D.
    Overall, Christopher M.
    Pandey, Kailash C.
    Ruland, Juergen
    Salvesen, Guy S.
    Shi, Yigong
    Smertenko, Andrei
    Stael, Simon
    Stahlberg, Jerry
    Fernanda Suarez, Maria
    Thome, Margot
    Tuominen, Hannele
    Van Breusegem, Frank
    van der Hoorn, Renier A. L.
    Vardi, Assaf
    Zhivotovsky, Boris
    Lam, Eric
    Bozhkov, Peter V.
    Classification and Nomenclature of Metacaspases and Paracaspases: No More Confusion with Caspases2020Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 77, nr 5, s. 927-929Artikel i tidskrift (Refereegranskat)
  • 13. Nicholls, Thomas J.
    et al.
    Spåhr, Henrik
    Jiang, Shan
    Siira, Stefan J.
    Koolmeister, Camilla
    Sharma, Sushma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kauppila, Johanna H. K.
    Jiang, Min
    Kaever, Volkhard
    Rackham, Oliver
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Falkenberg, Maria
    Filipovska, Aleksandra
    Larsson, Nils-Göran
    Gustafsson, Claes M.
    Dinucleotide Degradation by REXO2 Maintains Promoter Specificity in Mammalian Mitochondria2019Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 76, nr 5, s. 784-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Oligoribonucleases are conserved enzymes that degrade short RNA molecules of up to 5 nt in length and are assumed to constitute the final stage of RNA turnover. Here we demonstrate that REXO2 is a specialized dinucleotide-degrading enzyme that shows no preference between RNA and DNA dinucleotide substrates. A heart- and skeletal-muscle-specific knockout mouse displays elevated dinucleotide levels and alterations in gene expression patterns indicative of aberrant dinucleotide-primed transcription initiation. We find that dinucleotides act as potent stimulators of mitochondrial transcription initiation in vitro. Our data demonstrate that increased levels of dinucleotides can be used to initiate transcription, leading to an increase in transcription levels from both mitochondrial promoters and other, nonspecific sequence elements in mitochondrial DNA. Efficient RNA turnover by REXO2 is thus required to maintain promoter specificity and proper regulation of transcription in mammalian mitochondria.

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  • 14.
    Nissan, Tracy A
    et al.
    Biochemie-Zentrum der Universität Heidelberg.
    Galani, Kyriaki
    Maco, Bohumil
    Tollervey, David
    Aebi, Ueli
    Hurt, Ed
    A pre-ribosome with a tadpole-like structure functions in ATP-dependent maturation of 60S subunits2004Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 15, nr 2, s. 295-301Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 15.
    Nissan, Tracy
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Rajyaguru, Purusharth
    She, Meipei
    Song, Haiwei
    Parker, Roy
    Decapping activators in Saccharomyces cerevisiae act by multiple mechanisms2010Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 39, nr 5, s. 773-783Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 16. Novak, R
    et al.
    Charpentier, E
    Braun, J S
    Tuomanen, E
    Signal transduction by a death signal peptide: uncovering the mechanism of bacterial killing by penicillin.2000Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 5, nr 1, s. 49-57Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The binding of bactericidal antibiotics like penicillins, cephalosporins, and glycopeptides to their bacterial targets stops bacterial growth but does not directly cause cell death. A second process arising from the bacteria itself is necessary to trigger endogenous suicidal enzymes that dissolve the cell wall during autolysis. The signal and the trigger pathway for this event are completely unknown. Using S. pneumoniae as a model, we demonstrate that signal transduction via the two-component system VncR/S triggers multiple death pathways. We show that the signal sensed by VncR/S is a secreted peptide, Pep27, that initiates the cell death program. These data depict a novel model for the control of bacterial cell death.

  • 17.
    Rossmann, Marlies P
    et al.
    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
    Luo, Weijun
    Tsaponina, Olga
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Stillman, Bruce
    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
    A common telomeric gene silencing assay is affected by nucleotide metabolism2011Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 42, nr 1, s. 127-136Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Telomere-associated position-effect variegation (TPEV) in budding yeast has been used as a model for understanding epigenetic inheritance and gene silencing. A widely used assay to identify mutants with improper TPEV employs the URA3 gene at the telomere of chromosome VII-L that can be counterselected with 5-fluoroorotic acid (5-FOA). 5-FOA resistance has been inferred to represent lack of transcription of URA3 and therefore to represent heterochromatin-induced gene silencing. For two genes implicated in telomere silencing, POL30 and DOT1, we show that the URA3 telomere reporter assay does not reflect their role in heterochromatin formation. Rather, an imbalance in ribonucleotide reductase (RNR), which is induced by 5-FOA, and the specific promoter of URA3 fused to ADH4 at telomere VII-L are jointly responsible for the variegated phenotype. We conclude that metabolic changes caused by the drug employed and certain mutants being studied are incompatible with the use of certain prototrophic markers for TPEV.

  • 18. Sparks, Justin L
    et al.
    Chon, Hyongi
    Cerritelli, Susana M
    Kunkel, Thomas A
    Johansson, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Crouch, Robert J
    Burgers, Peter M
    RNase H2-Initiated Ribonucleotide Excision Repair2012Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 47, nr 6, s. 980-986Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ribonucleotides are incorporated into DNA by the replicative DNA polymerases at frequencies of about 2 per kb, which makes them by far the most abundant form of potential DNA damage in the cell. Their removal is essential for restoring a stable intact chromosome. Here, we present a complete biochemical reconstitution of the ribonucleotide excision repair (RER) pathway with enzymes purified from Saccharomyces cerevisiae. RER is most efficient when the ribonucleotide is incised by RNase H2, and further excised by the flap endonuclease FEN1 with strand displacement synthesis carried out by DNA polymerase δ, the PCNA clamp, its loader RFC, and completed by DNA ligase I. We observed partial redundancy for several of the enzymes in this pathway. Exo1 substitutes for FEN1 and Pol ε for Pol δ with reasonable efficiency. However, RNase H1 fails to substitute for RNase H2 in the incision step of RER.

  • 19.
    Sternberg, Samuel H
    et al.
    Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
    Richter, Hagen
    Charpentier, Emmanuelle
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Qimron, Udi
    Adaptation in CRISPR-Cas Systems2016Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 61, nr 6, s. 797-808Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins constitute an adaptive immune system in prokaryotes. The system preserves memories of prior infections by integrating short segments of foreign DNA, termed spacers, into the CRISPR array in a process termed adaptation. During the past 3 years, significant progress has been made on the genetic requirements and molecular mechanisms of adaptation. Here we review these recent advances, with a focus on the experimental approaches that have been developed, the insights they generated, and a proposed mechanism for self- versus non-self-discrimination during the process of spacer selection. We further describe the regulation of adaptation and the protein players involved in this fascinating process that allows bacteria and archaea to harbor adaptive immunity.

  • 20. Tyagi, Shweta
    et al.
    Chabes, Anna Lena
    Center for Integrative Genomics, University of Lausanne, Switzerland.
    Wysocka, Joanna
    Herr, Winship
    E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases.2007Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 27, nr 1, s. 107-119Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    E2F transcriptional regulators control human-cell proliferation by repressing and activating the transcription of genes required for cell-cycle progression, particularly the S phase. E2F proteins repress transcription in association with retinoblastoma pocket proteins, but less is known about how they activate transcription. Here, we show that the human G1 phase regulator HCF-1 associates with both activator (E2F1 and E2F3a) and repressor (E2F4) E2F proteins, properties that are conserved in insect cells. Human HCF-1-E2F interactions are versatile: their associations and binding to E2F-responsive promoters are cell-cycle selective, and HCF-1 displays coactivator properties when bound to the E2F1 activator and corepressor properties when bound to the E2F4 repressor. During the G1-to-S phase transition, HCF-1 recruits the mixed-lineage leukemia (MLL) and Set-1 histone H3 lysine 4 methyltransferases to E2F-responsive promoters and induces histone methylation and transcriptional activation. These results suggest that HCF-1 induces cell-cycle-specific transcriptional activation by E2F proteins to promote cell proliferation.

  • 21. Williams, Jessica S.
    et al.
    Smith, Dana J.
    Marjavaara, Lisette
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Lujan, Scott A.
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Kunkel, Thomas A.
    Topoisomerase 1-Mediated Removal of Ribonucleotides from Nascent Leading-Strand DNA2013Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 49, nr 5, s. 1010-1015Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    RNase H2-dependent ribonucleotide excision repair (RER) removes ribonucleotides incorporated during DNA replication. When RER is defective, ribonucleotides in the nascent leading strand of the yeast genome are associated with replication stress and genome instability. Here, we provide evidence that topoisomerase 1 (Top1) initiates an independent form of repair to remove ribonucleotides from genomic DNA. This Top1-dependent process activates the S phase checkpoint. Deleting TOP1 reverses this checkpoint activation and also relieves replication stress and genome instability in RER-defective cells. The results reveal an additional removal pathway for a very common lesion in DNA, and they imply that the "dirty" DNA ends created when Top1 incises ribonucleotides in DNA are responsible for the adverse consequences of ribonucleotides in RNase H2-defective cells.

  • 22. Yoshida, Kazumasa
    et al.
    Bacal, Julien
    Desmarais, Damien
    Padioleau, Ismaël
    Tsaponina, Olga
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pantesco, Véronique
    Dubois, Emeric
    Parrinello, Hugues
    Skrzypczak, Magdalena
    Ginalski, Krzysztof
    Lengronne, Armelle
    Pasero, Philippe
    The histone deacetylases sir2 and rpd3 act on ribosomal DNA to control the replication program in budding yeast2014Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 54, nr 4, s. 691-697Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In S. cerevisiae, replication timing is controlled by epigenetic mechanisms restricting the accessibility of origins to limiting initiation factors. About 30% of these origins are located within repetitive DNA sequences such as the ribosomal DNA (rDNA) array, but their regulation is poorly understood. Here, we have investigated how histone deacetylases (HDACs) control the replication program in budding yeast. This analysis revealed that two HDACs, Rpd3 and Sir2, control replication timing in an opposite manner. Whereas Rpd3 delays initiation at late origins, Sir2 is required for the timely activation of early origins. Moreover, Sir2 represses initiation at rDNA origins, whereas Rpd3 counteracts this effect. Remarkably, deletion of SIR2 restored normal replication in rpd3Δ cells by reactivating rDNA origins. Together, these data indicate that HDACs control the replication timing program in budding yeast by modulating the ability of repeated origins to compete with single-copy origins for limiting initiation factors.

  • 23.
    Yu, Chuanhe
    et al.
    Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, USA.
    Gan, Haiyun
    Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, USA.
    Han, Junhong
    Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, USA.
    Zhou, Zhi-Xiong
    Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, USA.
    Jia, Shaodong
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Farrugia, Gianrico
    Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, USA.
    Ordog, Tamas
    Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, USA.
    Zhang, Zhiguo
    Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, USA.
    Strand-specific analysis shows protein binding at replication forks and PCNA unloading from lagging strands when forks stall2014Ingår i: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 56, nr 4, s. 551-563Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In eukaryotic cells, DNA replication proceeds with continuous synthesis of leading-strand DNA and discontinuous synthesis of lagging-strand DNA. Here we describe a method, eSPAN (enrichment and sequencing of protein-associated nascent DNA), which reveals the genome-wide association of proteins with leading and lagging strands of DNA replication forks. Using this approach in budding yeast, we confirm the strand specificities of DNA polymerases delta and epsilon and show that the PCNA clamp is enriched at lagging strands compared with leading-strand replication. Surprisingly, at stalled forks, PCNA is unloaded specifically from lagging strands. PCNA unloading depends on the Elg1-containing alternative RFC complex, ubiquitination of PCNA, and the checkpoint kinases Mec1 and Rad53. Cells deficient in PCNA unloading exhibit increased chromosome breaks. Our studies provide a tool for studying replication-related processes and reveal a mechanism whereby checkpoint kinases regulate strand-specific unloading of PCNA from stalled replication forks to maintain genome stability.

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