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  • Dampening DNA damage checkpoint signalling via coordinated BRCT domain interactions
    Dampening DNA damage checkpoint signalling via coordinated BRCT domain interactions
    1. José R Cussiol1,
    2. Carolyn M Jablonowski1,
    3. Askar Yimit2,
    4. Grant W Brown2 and
    5. Marcus B Smolka*,1
    1. 1Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, USA
    2. 2Donnelly Centre and Department of Biochemistry, University of Toronto, Toronto, ON, Canada
    1. *Corresponding author. Tel: +1 607 255 0274; E‐mail: mbs266{at}cornell.edu

    The DNA repair scaffold proteins Slx4 and Rtt107 utilize a minimal multi‐BRCT‐domain module for phosphatase‐independent down‐regulation of DNA damage response signals in yeast.

    Synopsis

    The DNA repair scaffold proteins Slx4 and Rtt107 utilize a minimal multi‐BRCT‐domain module for phosphatase‐independent downregulation of DNA damage response signals in yeast.

    • Checkpoint dampening by the Rtt107‐Slx4‐Dpb11 complex relies on a ‘two‐site‐docking’ mechanism requiring phosphorylation sites on histone H2A and on the 9‐1‐1 clamp.

    • A minimal BRCT‐domain module (MBD) recapitulates the Rtt107‐Slx4‐Dpb11 complex role in checkpoint dampening and fully rescues MMS sensitivity of cells lacking Slx4.

    • MBD dampens Rad53 activation by specifically counteracting the checkpoint adaptor Rad9.

    • MBD transiently interacts with the 9‐1‐1 clamp and the Mus81 nuclease, but dampens the checkpoint independent of Mus81 function.

    • BRCT domain
    • checkpoint
    • DNA damage
    • Dpb11
    • Slx4
    • Received December 17, 2014.
    • Revision received March 5, 2015.
    • Accepted March 27, 2015.
    José R Cussiol, Carolyn M Jablonowski, Askar Yimit, Grant W Brown, Marcus B Smolka
  • REV7/MAD2L2: the multitasking maestro emerges as a barrier to recombination
    REV7/MAD2L2: the multitasking maestro emerges as a barrier to recombination
    1. Julian E Sale (jes{at}mrc-lmb.cam.ac.uk) 1
    1. 1MRC Laboratory of Molecular Biology, Cambridge, UK

    REV7/MAD2L2 plays important roles in translesion DNA synthesis and mitotic control. Two new papers extend its gamut by revealing its unexpected participation in pathway choice during DNA double‐strand break repair. By inhibiting 5′ DNA end resection downstream of 53BP1 and RIF1, REV7/MAD2L2 promotes non‐homologous end joining at the expense of homologous recombination. Importantly, loss of REV7/MAD2L2 renders PARP inhibitors ineffective in BRCA1‐deficient tumours, suggesting another possible mechanism for the acquisition of resistance to this important new class of drug.

    See also: G Xu et al and

    V Boersma et al

    Two new papers implicating REV7/MAD2L2 in DNA double strand break repair pathway choice further extend the impressive functional spectrum of this translesion synthesis and mitotic control factor.

    Julian E Sale
  • Repression of SRF target genes is critical for Myc‐dependent apoptosis of epithelial cells
    Repression of SRF target genes is critical for Myc‐dependent apoptosis of epithelial cells
    1. Katrin E Wiese1,,
    2. Heidi M Haikala2,,
    3. Björn von Eyss1,,
    4. Elmar Wolf1,
    5. Cyril Esnault3,
    6. Andreas Rosenwald4,5,
    7. Richard Treisman3,
    8. Juha Klefström2 and
    9. Martin Eilers*,1,5
    1. 1Biocenter Theodor Boveri Institute University of Würzburg, Würzburg, Germany
    2. 2Faculty of Medicine, Cancer Cell Circuitry Laboratory, Translational Cancer Biology Research Program and Institute of Biomedicine Biomedicum Helsinki University of Helsinki, Helsinki, Finland
    3. 3Cancer Research UK London Research Institute Lincoln's Inn Fields Laboratories Transcription Laboratory, London, UK
    4. 4Institute of Pathology University of Würzburg, Würzburg, Germany
    5. 5Comprehensive Cancer Center Mainfranken University of Würzburg, Würzburg, Germany
    1. *Corresponding author. Tel: +49 931 318 4111; E‐mail: martin.eilers{at}biozentrum.uni-wuerzburg.de
    1. These authors contributed equally to this work

    Oncogenic levels of Myc promote apoptosis by repressing cell adhesion molecules and Akt signaling in epithelial cells, counteracting serum‐response factor activity.

    Synopsis

    Myc‐driven apoptosis is a tumor‐suppressive mechanism that depends on Myc‐mediated repression of cell adhesion proteins and Akt signaling in epithelial cells.

    • Induction of apoptosis by Myc in epithelial cells requires association with Miz1.

    • Myc and Miz1 broadly repress genes involved in cell adhesion and migration.

    • Multiple Myc/Miz1‐repressed genes are targets of serum‐response factor (SRF).

    • Elevating SRF activity alleviates Myc/Miz1‐mediated repression and apoptosis.

    • Myc/Miz1 and SRF have antagonistic effects on Akt activity.

    • Akt
    • apoptosis
    • Miz1
    • Myc
    • Received November 5, 2014.
    • Revision received March 28, 2015.
    • Accepted March 30, 2015.
    Katrin E Wiese, Heidi M Haikala, Björn von Eyss, Elmar Wolf, Cyril Esnault, Andreas Rosenwald, Richard Treisman, Juha Klefström, Martin Eilers
  • The first murine zygotic transcription is promiscuous and uncoupled from splicing and 3′ processing
    The first murine zygotic transcription is promiscuous and uncoupled from splicing and 3′ processing
    1. Ken‐ichiro Abe1,,
    2. Ryoma Yamamoto1,,
    3. Vedran Franke2,,
    4. Minjun Cao1,
    5. Yutaka Suzuki3,4,
    6. Masataka G Suzuki1,
    7. Kristian Vlahovicek2,5,,
    8. Petr Svoboda*,6,
    9. Richard M Schultz*,7 and
    10. Fugaku Aoki*,1
    1. 1Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan
    2. 2Bioinformatics Group, Division of Biology, Faculty of Science, Zagreb University, Zagreb, Croatia
    3. 3Department of Medical Genome Science, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan
    4. 4The University of Tokyo, Tokyo, Japan
    5. 5Department of Informatics, University of Oslo, Oslo, Norway
    6. 6Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    7. 7Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
    1. * Corresponding author. Tel: +420 241063147; E‐mail: svobodap{at}img.cas.cz

      Corresponding author. Tel: +1 215 898 7869; E‐mail: rschultz{at}sas.upenn.edu

      Corresponding author. Tel: +81 471 36 3695; Fax: +81 471 36 3698; E‐mail: aokif{at}k.u-tokyo.ac.jp

    1. These authors contributed equally to this work

    2. Corresponding author for computational biology

    Transcriptome analysis in mouse 1‐cell embryos reveals widespread transcription of intergenic regions devoid of core‐promoter elements. The resulting RNAs, possibly involved in chromatin remodeling, are poorly processed to prevent aberrant expression.

    Synopsis

    Transcriptome analysis in mouse 1‐cell embryos reveals widespread transcription of intergenic regions devoid of core‐promoter elements. The resulting RNAs, possibly involved in chromatin remodeling, are poorly processed to prevent aberrant expression.

    • The first round of zygotic transcription occurs at low levels and is genome‐wide.

    • Zygotic transcription is opportunistic and can occur without defined core‐promoter elements.

    • Gene transcription in the zygote is uncoupled from splicing and 3′ processing, leaving most transcripts nonfunctional.

    • Genes transcribed in zygotes often yield functional mRNAs in 2‐cell embryos.

    • gene expression
    • preimplantation mouse embryo
    • pre‐mRNA splicing
    • RNA‐Seq
    • transcription
    • Received November 25, 2014.
    • Revision received March 9, 2015.
    • Accepted March 19, 2015.
    Ken‐ichiro Abe, Ryoma Yamamoto, Vedran Franke, Minjun Cao, Yutaka Suzuki, Masataka G Suzuki, Kristian Vlahovicek, Petr Svoboda, Richard M Schultz, Fugaku Aoki
  • USP18 lack in microglia causes destructive interferonopathy of the mouse brain
    USP18 lack in microglia causes destructive interferonopathy of the mouse brain
    1. Tobias Goldmann1,
    2. Nicolas Zeller1,
    3. Jenni Raasch1,
    4. Katrin Kierdorf1,
    5. Kathrin Frenzel1,
    6. Lars Ketscher1,
    7. Anja Basters1,
    8. Ori Staszewski1,
    9. Stefanie M Brendecke1,
    10. Alena Spiess1,
    11. Tuan Leng Tay1,
    12. Clemens Kreutz2,
    13. Jens Timmer2,3,
    14. Grazia MS Mancini4,
    15. Thomas Blank1,
    16. Günter Fritz1,
    17. Knut Biber5,6,
    18. Roland Lang7,
    19. Danielle Malo8,
    20. Doron Merkler9,
    21. Mathias Heikenwälder10,
    22. Klaus‐Peter Knobeloch1, and
    23. Marco Prinz*,1,3,
    1. 1Institute of Neuropathology, University of Freiburg, Freiburg, Germany
    2. 2Institute of Physics & Center for Systems Biology (ZBSA), University of Freiburg, Freiburg, Germany
    3. 3BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany
    4. 4Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
    5. 5Department of Psychiatry, University of Freiburg, Freiburg, Germany
    6. 6Department of Neuroscience, University Medical Center Groningen, Groningen, The Netherlands
    7. 7Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Erlangen, Germany
    8. 8Department of Human Genetics, McGill University, Montreal, QC, Canada
    9. 9Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
    10. 10Institute of Virology, Technische Universität München/Helmholtz‐Zentrum Munich, München, Germany
    1. *Corresponding author. Tel: +49 761 270 51050; Fax: +49 761 270 50500; E‐mail: marco.prinz{at}uniklinik-freiburg.de
    1. These authors contributed equally to this work

    The non‐catalytic anti‐inflammatory function of a deubiquitination enzyme plays a key role in preventing microglia activation and neuroinflammation in mouse brains.

    Synopsis

    This study identifies Usp18 as a new critical negative regulator of microglia activation and demonstrates a protective role of Usp18 for microglia function by regulating IFN signaling.

    • The protease USP18 is expressed in white matter microglia.

    • Loss of USP18 induces white matter microglia activation and leads to microgliopathy.

    • Microglia activation in the absence of USP18 is due to prolonged STAT1 phosphorylation.

    • Constitutive IFN type I signaling in microglia during steady state.

    • The Ifnar2 interaction domain rather then the protease function of USP19 controls microglia activation.

    • EAE
    • microglia
    • multiple sclerosis
    • type I interferon
    • Usp18
    • Received December 12, 2014.
    • Revision received March 3, 2015.
    • Accepted March 17, 2015.
    Tobias Goldmann, Nicolas Zeller, Jenni Raasch, Katrin Kierdorf, Kathrin Frenzel, Lars Ketscher, Anja Basters, Ori Staszewski, Stefanie M Brendecke, Alena Spiess, Tuan Leng Tay, Clemens Kreutz, Jens Timmer, Grazia MS Mancini, Thomas Blank, Günter Fritz, Knut Biber, Roland Lang, Danielle Malo, Doron Merkler, Mathias Heikenwälder, Klaus‐Peter Knobeloch, Marco Prinz
  • Expression of Ca2+‐permeable two‐pore channels rescues NAADP signalling in TPC‐deficient cells
    <div xmlns="http://www.w3.org/1999/xhtml">Expression of Ca<sup>2+</sup>‐permeable two‐pore channels rescues NAADP signalling in TPC‐deficient cells</div>
    1. Margarida Ruas1,,
    2. Lianne C Davis1,,
    3. Cheng‐Chang Chen2,
    4. Anthony J Morgan1,
    5. Kai‐Ting Chuang14,
    6. Timothy F Walseth3,
    7. Christian Grimm2,
    8. Clive Garnham1,
    9. Trevor Powell1,
    10. Nick Platt1,
    11. Frances M Platt1,
    12. Martin Biel2,
    13. Christian Wahl‐Schott2,
    14. John Parrington*,1 and
    15. Antony Galione*,1
    1. 1Department of Pharmacology, University of Oxford, Oxford, UK
    2. 2Center for Integrated Protein Science CIPS‐M and Department of Pharmacy – Center for Drug Research, Ludwig‐Maximilians‐Universität München, München, Germany
    3. 3Pharmacology Department, University of Minnesota, Minneapolis, MN, USA
    4. 4The Center for Immunology and Inflammatory Diseases, Harvard Medical School, Boston, MA, USA
    1. * Corresponding author. Tel: +44 1865 271591; Fax: +44 1865 271853; E‐mail: john.parrington{at}pharm.ox.ac.uk

      Corresponding author. Tel: +44 1865 271633; Fax: +44 1865 271853; E‐mail: antony.galione{at}pharm.ox.ac.uk

    1. These authors contributed equally to this work

    By presenting a new double‐knockout mouse model this study demonstrates that two‐pore channels (TPCs) are responsible for NAADP‐dependent Ca2+ release from endo‐lysosomes.

    Synopsis

    By presenting a new double‐knockout mouse model this study demonstrates that two‐pore channels (TPCs) are responsible for NAADP‐dependent Ca2+ release from endo‐lysosomes.

    • Endogenous two‐pore channels (TPCs) are essential for NAADP‐stimulated Ca2+ currents and Ca2+ release.

    • Re‐expression of TPCs in validated null‐background cells restores NAADP sensitivity.

    • Truncated TPC1 and TPC2 proteins—potentially expressed in other reported TPC knockouts—are still functional.

    • TPCs are not required for high‐affinity NAADP‐binding.

    • PI(3,5)P2 is a promiscuous modulator of endo‐lysosomal channels.

    • Ca2+
    • electrophysiology
    • endo‐lysosome
    • NAADP
    • TPC
    • Received September 10, 2014.
    • Revision received March 6, 2015.
    • Accepted March 11, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Margarida Ruas, Lianne C Davis, Cheng‐Chang Chen, Anthony J Morgan, Kai‐Ting Chuang, Timothy F Walseth, Christian Grimm, Clive Garnham, Trevor Powell, Nick Platt, Frances M Platt, Martin Biel, Christian Wahl‐Schott, John Parrington, Antony Galione
  • Tregs strip dendritic cells of CD70 to regulate Th1 differentiation
    Tregs strip dendritic cells of CD70 to regulate Th1 differentiation
    1. Lukasz Wojciech1 and
    2. Leszek Ignatowicz (lignatowicz{at}gru.edu) 1
    1. 1Department of Medicine, Center for Biotechnology and Genomic Medicine Georgia Regents University, Augusta, GA, USA

    When the immune system encounters an antigen, the response can result in the mobilization of effector cells or in tolerance. The outcome is largely dependent on immunosuppressive CD4 T cells that express the transcription factor Foxp3 (Tregs). Yet, how Tregs control different immune effector cells remains elusive. In this issue of The EMBO Journal, Dhainaut et al report on a novel mechanism used by Tregs to prevent differentiation of naïve CD4 T cells to proinflammatory Th1CD4 (Th1) effectors.

    See also: M Dhainaut et al

    A recent study reveals a new mechanism by which regulatory T cells suppress excessive inflammatory responses.

    Lukasz Wojciech, Leszek Ignatowicz