RNA Biology
- The unfolded protein response is shaped by the NMD pathway
- Rachid Karam14,
- Chih‐Hong Lou1,
- Heike Kroeger2,
- Lulu Huang15,
- Jonathan H Lin2 and
- Miles F Wilkinson*,1,3
- 1Department of Reproductive Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA
- 2Department of Pathology, School of Medicine, University of California San Diego, La Jolla, CA, USA
- 3Institute of Genomic Medicine, University of California San Diego, La Jolla, CA, USA
- 4Ambry Genetics, Aliso Viejo, CA, USA
- 5 ISIS Pharmaceuticals, Carlsbad, CA, USA
- ↵*Corresponding author. Tel: +1 858 822 4819; E‐mail: mfwilkinson{at}ucsd.edu
The threshold for UPR triggering and its timely termination are shown to depend on the nonsense‐mediated RNA decay (NMD) pathway. NMD regulates the mRNAs of several UPR components, which underpins this effect.
Synopsis
This study shows that both the threshold for triggering the unfolded protein response (UPR) and its timely termination depend on the nonsense‐mediated RNA decay (NMD) pathway. The mRNAs of several UPR components are directly regulated through NMD, which underpins this effect.
UPR induction in response to innocuous stress is prevented by the NMD RNA decay pathway.
NMD is downregulated in response to bona fide stress to permit a maximal UPR response.
NMD acts by driving the rapid decay of several UPR component transcripts, including IRE1α mRNA.
NMD promotes timely UPR termination, thereby reducing the likelihood of stress‐induced apoptosis.
EMBO Reports (2015) 16: 599–609
- Received October 8, 2014.
- Revision received February 13, 2015.
- Accepted February 24, 2015.
- © 2015 The Authors
- Potent degradation of neuronal miRNAs induced by highly complementary targets
- Manuel de la Mata1,
- Dimos Gaidatzis1,2,
- Mirela Vitanescu15,
- Michael B Stadler1,2,3,
- Corinna Wentzel46,
- Peter Scheiffele4,
- Witold Filipowicz*,1,3 and
- Helge Großhans*,1
- 1Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- 2Swiss Institute of Bioinformatics, Basel, Switzerland
- 3University of Basel, Basel, Switzerland
- 4Biozentrum, University of Basel, Basel, Switzerland
- 5Department of Anaesthesiology and Pain Medicine, Inselspital, University of Bern, Bern, Switzerland
- 6Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
- ↵*
Corresponding author. Tel: +41 61 697 6993; E‐mail: witold.filipowicz{at}fmi.ch
Corresponding author. Tel: +41 61 697 6675; E‐mail: helge.grosshans{at}fmi.ch
This quantitative study of target‐directed miRNA degradation (TDMD) reveals its potency in primary neurons and distinguishes TDMD and mRNA degradation as independent processes, the balance of which can be tilted toward depletion of even abundant miRNAs by appropriate target design.
Synopsis
This quantitative study of target‐directed miRNA degradation (TDMD) reveals its potency in primary neurons and distinguishes TDMD and mRNA degradation as independent processes, the balance of which can be tilted toward depletion of even abundant miRNAs by appropriate target design.
Target‐induced non‐templated nucleotide addition (tailing) occurs on miRNAs, while they are bound to Argonaute.
TDMD and mRNA silencing are independent processes, permitting one target to induce degradation of several miRNA molecules.
mRNA silencing, but not TDMD, requires cooperativity among multiple target sites to reach high efficiency.
EMBO Reports (2015) 16: 500–511
- Received January 8, 2015.
- Revision received January 21, 2015.
- Accepted January 26, 2015.
- © 2015 The Authors
- IP3 signalling regulates exogenous RNAi in Caenorhabditis elegans
- Anikó I Nagy14†,
- Rafael P Vázquez‐Manrique2,3,†,
- Marie Lopez15,
- Christo P Christov1,
- María Dolores Sequedo2,3,
- Mareike Herzog16,
- Anna E Herlihy17,
- Maxime Bodak18,
- Roxani Gatsi19 and
- Howard A Baylis*,1
- 1Department of Zoology, University of Cambridge, Cambridge, UK
- 2Research Group in Molecular, Cellular and Genomic Biomedicine, Health Research Institute‐La Fe, Valencia, Spain
- 3Centre for Biomedical Network Research on Rare Diseases (CIBERER), Valencia, Spain
- 4Heart and Vascular Centre, Semmelweis University, Budapest, Hungary
- 5 Unit Human Evolutionary Genetics, Institut Pasteur, Paris, France
- 6 Wellcome Trust Sanger Institute, Cambridge, UK
- 7 MRC Laboratory for Molecular Cell Biology, University College London, London, UK
- 8 ETH Zurich, Institute of Molecular Health Sciences, Zurich, Switzerland
- 9 Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide, Sevilla, Spain
- ↵*Corresponding author. Tel: +44 1223 336630; Fax: +44 1223 336676; E‐mail: hab28{at}cam.ac.uk
-
↵† These authors contributed equally to this work
Reducing intracellular IP3 signaling enhances RNAi sensitivity in C. elegans through a function of IP3 in the intestine. This suggests that an animal's physiology or environment may influence its RNAi responses.
Synopsis
Reducing intracellular IP3 signaling enhances RNAi sensitivity in C. elegans through a function of IP3 in the intestine. This suggests that an animal's physiology or environment may influence its RNAi responses.
Altering intracellular IP3 signalling modifies sensitivity to RNAi in different tissues.
Tissue‐specific rescue experiments suggest IP3 functions in the intestine to control RNAi sensitivity throughout the animal.
IP3 signalling mutations can further enhance the sensitivity of existing RNAi hypersensitive strains.
EMBO Reports (2015) 16: 341–350
- Received September 15, 2014.
- Revision received December 4, 2014.
- Accepted December 15, 2014.
- © 2015 The Authors
- The RNA‐binding protein Arrest (Bruno) regulates alternative splicing to enable myofibril maturation in Drosophila flight muscle
- Maria L Spletter1,
- Christiane Barz1,
- Assa Yeroslaviz1,
- Cornelia Schönbauer1,
- Irene R S Ferreira1,
- Mihail Sarov2,
- Daniel Gerlach34,
- Alexander Stark3,
- Bianca H Habermann1 and
- Frank Schnorrer*,1
- 1Max Planck Institute of Biochemistry, Martinsried, Germany
- 2Max Planck Institute of Cell Biology and Genetics, Dresden, Germany
- 3Research Institute of Molecular Pathology (IMP) Vienna Biocenter (VBC), Vienna, Austria
- 4Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
- ↵*Corresponding author. Tel: +49 89 8578 2434; E‐mail: schnorrer{at}biochem.mpg.de
Arrest (Bruno) regulates flight muscle‐specific splicing of a large number of genes encoding for sarcomeric proteins. Correct expression of these flight muscle‐specific isoforms is essential to build the contractile apparatus of fibrillar flight muscles.
Synopsis
Arrest (Bruno) regulates flight muscle‐specific splicing of a large number of genes encoding for sarcomeric proteins. Correct expression of these flight muscle‐specific isoforms is essential to build the contractile apparatus of fibrillar flight muscles.
Spalt major induces expression of the RNA binding protein Arrest in flight muscles.
Arrest induces fibrillar muscle‐specific splicing of sarcomeric protein isoforms in flight muscles.
Arrest is essential for normal myofibril maturation and sarcomere growth to prevent hyper‐contraction in adult flight muscles.
EMBO Reports (2015) 16: 178–191
- Received October 27, 2014.
- Revision received November 25, 2014.
- Accepted December 2, 2014.
- © 2014 The Authors. Published under the terms of the CC BY NC ND 4.0 license
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
- RNA‐processing proteins regulate Mec1/ATR activation by promoting generation of RPA‐coated ssDNA
- Nicola Manfrini1,
- Camilla Trovesi1,
- Maxime Wery2,
- Marina Martina1,
- Daniele Cesena1,
- Marc Descrimes2,
- Antonin Morillon*,2,
- Fabrizio d'Adda di Fagagna*,3,4 and
- Maria Pia Longhese*,1
- 1Dipartimento di Biotecnologie e Bioscienze, Università di Milano‐Bicocca, Milan, Italy
- 2Institut Curie, CNRS UMR3244 Université Pierre et Marie Curie, Paris Cedex 05, France
- 3IFOM Foundation‐FIRC Institute of Molecular Oncology Foundation, Milan, Italy
- 4Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy
- ↵*
Corresponding author. Tel: +33 156246570; Fax: +33 156246674; E‐mail: antonin.morillon{at}curie.fr
Corresponding author. Tel: +39 02574303227; Fax: +39 02574303231; E‐mail: fabrizio.dadda{at}ifom.eu
Corresponding author. Tel: +39 0264483425; Fax: +39 0264483565; E‐mail: mariapia.longhese{at}unimib.it
The S. cerevisiae RNA decay factors Xrn1, Rrp6 and Trf4 facilitate Mec1/ATR activation by promoting the formation of RPA‐coated ssDNA at dsDNA breaks.
Synopsis
The S. cerevisiae RNA decay factors Xrn1, Rrp6 and Trf4 facilitate Mec1/ATR activation by promoting the formation of RPA‐coated ssDNA at dsDNA breaks.
Xrn1 promotes the formation of single‐stranded DNA at the ends of double‐stranded DNA breaks.
Rrp6 and Trf4 contribute to the recruitment of RPA and Mec1/ATR to the single‐stranded DNA ends.
EMBO Reports (2015) 16: 221–231
- Received August 18, 2014.
- Revision received November 21, 2014.
- Accepted November 24, 2014.
- © 2014 The Authors
- Identification and characterization of novel factors that act in the nonsense‐mediated mRNA decay pathway in nematodes, flies and mammals
- Angela Casadio1,
- Dasa Longman*,1,
- Nele Hug1,
- Laurent Delavaine1,
- Raúl Vallejos Baier2,
- Claudio R Alonso2 and
- Javier F Cáceres*,1
- 1MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital University of Edinburgh, Edinburgh, UK
- 2School of Life Sciences, University of Sussex, Brighton, UK
- ↵*
Corresponding author. Tel: +44 131 332 2471; Fax: +44 131 467 8456; E‐mail: Dasa.Longman{at}igmm.ed.ac.uk
Corresponding author. Tel: +44 131467 8426; Fax: +44 131 467 8456; E‐mail: Javier.Caceres{at}igmm.ed.ac.uk
A genome‐wide RNAi screen in C. elegans identifies five novel NMD genes that are required for development and conserved throughout evolution, suggesting that the regulation of the NMD pathway is more complex than previously thought.
Synopsis
A genome‐wide RNAi screen in C. elegans identifies five novel NMD genes that are required for development and conserved throughout evolution, suggesting that the regulation of the NMD pathway is more complex than previously thought.
Five novel NMD factors that are also essential for development are identified in C. elegans.
Two of the human orthologs, GNL2 (ngp‐1) and SEC13 (npp‐20), are also required for NMD in human cells.
The C. elegans gene noah‐2, which is present in Drosophila melanogaster but absent in humans, is a tissue‐specific NMD factor in fruit flies.
EMBO Reports (2015) 16: 71–78
- Received June 17, 2014.
- Revision received October 30, 2014.
- Accepted November 3, 2014.
- © 2014 The Authors. Published under the terms of the CC BY 4.0 license
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.
- Micro‐RNAs meet epigenetics to make for better brains
Recent studies have highlighted the importance of regulatory non‐coding RNAs and epigenetics in controlling the differentiation of somatic stem cells. Two major pathways characterize these fields: micro‐RNAs (miRNAs) and DNA methylation. In this issue of EMBO Reports, Lv et al show that during mammalian corticogenesis, miR‐15b inhibits cytosine demethylation by targeting Tet3, a key methylcytosine dioxygenase. This leads to the epigenetic downregulation of cyclin D1. As a result, cell cycle and differentiation of neural progenitors are altered, promoting their switch to neurogenesis. Hence, Lv et al elegantly bring together miRNAs and DNA methylation in the cell cycle control of neural progenitors and neurogenesis.
See also: X Lv et al (December 2014)
A study in this issue shows that miR‐15b directly targets TET3 to epigenetically repress cyclin D1 expression and neural progenitor cell proliferation, which promotes neurogenesis in the mouse neocortex.
- © 2014 The Authors
- The RtcB RNA ligase is an essential component of the metazoan unfolded protein response
- Sara Guckian Kosmaczewski1,†,
- Tyson James Edwards1,†,
- Sung Min Han1,
- Matthew J Eckwahl2,
- Benjamin Isaiah Meyer1,
- Sally Peach3,
- Jay R Hesselberth3,
- Sandra L Wolin2 and
- Marc Hammarlund*,1
- 1Department of Genetics and Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT, USA
- 2Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA
- 3Biochemistry & Molecular Genetics Department, University of Colorado School of Medicine, Aurora, CO, USA
- ↵*Corresponding author. Tel: +1 203 737 4181; E‐mail: marc.hammarlund{at}yale.edu
-
↵† These authors contributed equally to this work
Work in C. elegans shows that RtcB is the RNA ligase for xbp‐1 splicing in the IRE‐1 branch of the UPR. RtcB also ligates endogenous tRNA substrates and promotes lifespan and development.
Synopsis
Work in C. elegans shows that RtcB is the RNA ligase for xbp‐1 splicing in the IRE‐1 branch of the UPR. RtcB also ligates endogenous tRNA substrates and promotes lifespan and development.
RtcB ligates endogenous intron‐containing tRNAs in vivo.
RtcB is the sole ligase for xbp‐1 splicing in the UPR.
The tRNA and xbp‐1 functions of RtcB can be separated using animals engineered to express intron‐free tRNAs.
EMBO Reports (2014) 15: 1278–1285
- Received September 2, 2014.
- Revision received September 25, 2014.
- Accepted September 26, 2014.
- © 2014 The Authors
- MicroRNA‐15b promotes neurogenesis and inhibits neural progenitor proliferation by directly repressing TET3 during early neocortical development
- 1State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- ↵*Corresponding author. Tel: +86 10 64806335; E‐mail: jwjiao{at}ioz.ac.cn
-
↵† These authors contributed equally to this work
This study shows that miR‐15b targets TET3 and that miR‐15b and TET3 contribute to maintain the NPC pool during early neocortical development.
Synopsis
This study shows that miR‐15b targets TET3 and that miR‐15b and TET3 contribute to maintain the NPC pool during early neocortical development.
miR‐15b is expressed in neural progenitors, represses NPC proliferation, increases the number of basal progenitors, and promotes neurogenesis.
miR‐15b directly targets TET3 to epigenetically repress cyclin D1 expression and NPC proliferation.
EMBO Reports (2014) 15: 1305–1314
- Received April 16, 2014.
- Revision received September 14, 2014.
- Accepted September 22, 2014.
- © 2014 The Authors
- E2F1 induces miR‐224/452 expression to drive EMT through TXNIP downregulation
- Susanne Knoll1,
- Katharina Fürst1,
- Bhavani Kowtharapu1,
- Ulf Schmitz2,
- Stephan Marquardt1,
- Olaf Wolkenhauer2,
- Hubert Martin3 and
- Brigitte M Pützer*,1
- 1Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany
- 2Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany
- 3Department of Neuropathology, University Hospital Charité, Berlin, Germany
- ↵*Corresponding author. Tel: +49 381 494 5066/68; Fax: +49 381 494 5062; E‐mail: brigitte.puetzer{at}med.uni-rostock.de
The E2F1‐miR‐244/452‐TXNIP pathway is shown to be crucial for melanoma invasion and metastasis in vivo. By activating the expression of miR‐224/452, E2F1 leads to the downregulation of its inhibitor, TXNIP, and induces EMT.
Synopsis
The E2F1‐miR‐244/452‐TXNIP pathway is shown to be crucial for melanoma invasion and metastasis in vivo. By activating the expression of miR‐224/452, E2F1 leads to the downregulation of its inhibitor, TXNIP, and induces EMT.
In early primary tumors, high levels of TXNIP restrict E2F1 activity through p16 activation and subsequent inhibition of RB.
Increasingly high levels of E2F1 during cancer progression lead to the transcriptional upregulation of the miR‐224/452 cluster.
miR‐224 and miR‐452 repress the expression of TXNIP to induce E2F1‐dependent EMT and invasion.
EMBO Reports (2014) 15: 1315–1329
- Received September 1, 2014.
- Revision received September 18, 2014.
- Accepted September 19, 2014.
- © 2014 The Authors
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