RNA metabolism

  • Article
    | Open Access

    RNA binding proteins are key regulators of alternative splicing. Here, Best et al. show that the human Tra2α and Tra2ß RNA binding proteins jointly contribute to the control of constitutive and alternative splicing events to regulate essential biological processes including the response to DNA damage.

    • Andrew Best
    • , Katherine James
    •  & David J. Elliott
  • Article
    | Open Access

    Common methods to detect adenosine-to-inosine RNA editing sites rely on mapping short RNA reads to the genome while allowing only a limited number of mismatches. Here, Porath et al. present a novel RNA-seq based approach to identify hyper-edited reads that significantly expands the RNA editome.

    • Hagit T. Porath
    • , Shai Carmi
    •  & Erez Y. Levanon
  • Article
    | Open Access

    RNA sequencing has enabled the global analysis of both gene expression levels and splicing events. Here, the authors develop a multivariate approach that is able to identify SNPs that influence splicing, and investigate the overlap of these with functional domains across the genome, including previously identified GWAS signals.

    • Jean Monlong
    • , Miquel Calvo
    •  & Roderic Guigó
  • Article
    | Open Access

    The exosome is responsible for mRNA degradation, which is an important step in the regulation of gene expression. Here the authors report that homozygous missense mutations in the exosome subunit, EXOSC8, may cause neurodegenerative disease in infants through the dysregulation of myelin expression.

    • Veronika Boczonadi
    • , Juliane S. Müller
    •  & Rita Horvath
  • Article |

    Frameshift mutations in the protein polyglutamine tract-binding protein 1 (PQBP1) are believed to cause X-linked mental retardation. Here, Mizuguchi et al.present the crystal structure of a C-terminal fragment of PQBP1 in complex with the spliceosomal protein U5–15kD, and show details of this interaction that can lead to mechanistic insights into the disease.

    • Mineyuki Mizuguchi
    • , Takayuki Obita
    •  & Hitoshi Okazawa
  • Article
    | Open Access

    Ire1 is an effector of the unfolded protein response that is activated upon stress to maintain protein homeostasis. Here, Prischi et al. demonstrate that phosphorylation of Ire1 within its kinase activation loop increases its RNAse activity, thus identifying a regulatory cross-talk between the two domains.

    • Filippo Prischi
    • , Piotr R. Nowak
    •  & Maruf M. U. Ali
  • Article
    | Open Access

    Telomerase activity can be regulated by alternative splicing of its catalytic subunit TERT. Here, Wong et al. demonstrate that TERTsplicing is regulated via RNA:RNA pairing of repetitive intronic sequences with the pre-mRNA, thus revealing a new function for conserved elements embedded within introns.

    • Mandy S. Wong
    • , Jerry W. Shay
    •  & Woodring E. Wright
  • Article |

    In eukaryotic cells, export of unprocessed pre-mRNAs is prevented by the nuclear surveillance machinery. Here Hackmann et al.identify the SR proteins Gbp2 and Hrb1 as two novel quality control factors for spliced mRNAs that determine their degradation or nuclear export.

    • Alexandra Hackmann
    • , Haijia Wu
    •  & Heike Krebber
  • Article
    | Open Access

    Human mRNA transcripts possess a 5' cap structure that is modified by methylation. Here, Smietanski et al.present the structures of human methyltransferases responsible for this reaction, revealing key differences to their viral counterparts and thereby providing a framework for targeted drug design.

    • Miroslaw Smietanski
    • , Maria Werner
    •  & Janusz M. Bujnicki
  • Article |

    Whether microRNA processing mediated by Dicer is regulated in a cell-cycle-dependent manner is unknown. Here, Chen et al.show that Cyclin D1, which is important in the control of the cell cycle, regulates the expression of Dicer, and that Cyclin D1 and Dicer expression levels correlate in breast cancer.

    • Zuoren Yu
    • , Liping Wang
    •  & Richard G. Pestell
  • Article |

    The Hoppel transposable element mediates heterochromatin formation in Drosophila. Here Savva et al. report that the RNA-editing enzyme, ADAR, edits a long double-stranded RNA generated by the Hoppeltransposon, thereby regulating heterochromatin formation and gene expression.

    • Yiannis A. Savva
    • , James E. C. Jepson
    •  & Robert A. Reenan
  • Article
    | Open Access

    Bacterial endonuclease V enzymes are characterized as DNA repair proteins. Here the authors show that human endonuclease V is an inosine-specific ribonuclease, indicating a role for this enzyme in normal RNA metabolism rather than DNA repair.

    • Erik Sebastian Vik
    • , Meh Sameen Nawaz
    •  & Ingrun Alseth
  • Article
    | Open Access

    In Escherichia coli, the highly conserved enzyme endonuclease V has a role in DNA repair. Here the authors show that human endonuclease V is an inosine 3' endoribonuclease and that Tudor Staphylococcal nuclease enhances this activity, suggesting a role for human endonuclease V in RNA metabolism.

    • Yoko Morita
    • , Toshihiro Shibutani
    •  & Isao Kuraoka
  • Article |

    A central, imperfect duplex RNA secondary structure is generally required for site-specific adenosine-to-inosine RNA editing by ADAR enzymes. Rieder et al. show in Drosophila that conserved and complex long-range RNA tertiary structures form in vivoand can also regulate specific RNA-editing events by ADAR enzymes.

    • Leila E. Rieder
    • , Cynthia J. Staber
    •  & Robert A. Reenan
  • Article
    | Open Access

    The thermodynamics of unwinding polynucleotide duplexes can be determined from energy changes for DNA and mRNA interactions. Here the authors show that the ratio between mRNA/DNA and DNA/DNA duplex stability upstream of the 3′- spice sites is a characteristic that can contribute to intron–exon recognition.

    • Marina N. Nedelcheva-Veleva
    • , Mihail Sarov
    •  & Stoyno S. Stoynov
  • Article |

    Splicing factors, such as the protein SRSF3, regulate mRNA metabolism but are hard to study in vivobecause genetic kockouts are usually lethal. Here, Sen and colleagues create mice with a hepatocyte-specific knockout of Srsf3 and demonstrate its role in hepatocyte differentiation and liver function.

    • Supriya Sen
    • , Hassan Jumaa
    •  & Nicholas J. G. Webster
  • Article
    | Open Access

    Alternative splicing at the Drosophila Down syndrome cell adhesion molecule gene generates 38,016 isoforms, and underlies self-avoidance of growing neurons. Wang et al. identify a structure in the DSCAM mRNA that ensures mutually exclusive splicing and observe expansion of the structure with increasing number of exons during arthropod evolution.

    • Xuebin Wang
    • , Guoli Li
    •  & Yongfeng Jin
  • Article |

    The TREX complex and Nxf1 are involved in the export of mRNA from the nucleus but the precise molecular function of TREX is unclear. Here, the TREX components Aly and Thoc5 are shown to bind to Nxf1 resulting in a change in Nxf1 conformation that permits binding to mRNA and nuclear export.

    • Nicolas Viphakone
    • , Guillaume M. Hautbergue
    •  & Stuart A. Wilson
  • Article |

    It is unclear where in the nucleus splicing takes place and how much occurs post-transcriptionally. Using antibodies raised against a phosphorylated splicing factor, Girardet al. show that the majority of splicing occurs co-transcriptionally and that post-transcriptional splicing occurs in nuclear speckles.

    • Cyrille Girard
    • , Cindy L. Will
    •  & Reinhard Lührmann
  • Article
    | Open Access

    Synaptic GTPase-activating protein, SynGAP, is a postsynaptic signalling protein that can regulate synaptic function. McMahonet al. express different SynGAP isoforms in neurons and find that the effect on synaptic strength depends on alternative promoter usage and alternative splicing of the C-terminus.

    • A.C. McMahon
    • , M.W. Barnett
    •  & P.C. Kind
  • Article
    | Open Access

    Phosphorylation of the carboxy-terminal domain of RNA polymerase II is important for controlling gene transcription. In this study, the transcription elongation factor Tefb is shown to phosphorylate serine-5 and its activity is enhanced when the polymerase is already phosphorylated on serine-7.

    • Nadine Czudnochowski
    • , Christian A. Bösken
    •  & Matthias Geyer
  • Article |

    Adars are adenosine deaminases that act on RNAs, including those encoding proteins involved in neuronal transmission and also Adar RNA. Here, Savvaet al. engineered knock-in Drosophila mutants with altered Adar autoediting and found that this changed the spectrum of adenosine deamination and Drosophilabehaviour.

    • Yiannis A. Savva
    • , James E.C Jepson
    •  & Robert A. Reenan
  • Article
    | Open Access

    The appearance of a new intron that splits an exon without disrupting the corresponding peptide sequence is a rare event in vertebrate genomes. Hellstenet al.demonstrate that, under certain circumstances, a functional intron can be produced in a single step by segmental genomic duplication.

    • Uffe Hellsten
    • , Julie L. Aspden
    •  & Daniel S. Rokhsar
  • Article
    | Open Access

    RNA editing is important in regulating neuronal excitability, and a specific editing event has been shown to alter the permeation pathway of voltage-gate potassium channels. Gonzalezet al.find that the tip of the channel's inactivation gate makes a direct hydrophobic interaction with the edited position.

    • Carlos Gonzalez
    • , Angelica Lopez-Rodriguez
    •  & Miguel Holmgren
  • Article
    | Open Access

    ADAR enzymes edit double-stranded RNA, converting adenosines to inosines, and are essential for neuronal function. Eggingtonet al. quantify edit sites in RNA using a Sanger sequencing protocol and use the resulting data to develop algorithms to predict RNA edit sites.

    • Julie M. Eggington
    • , Tom Greene
    •  & Brenda L. Bass
  • Article
    | Open Access

    Duchenne muscular dystrophy is caused by a loss of thedystrophin gene, and control of dystrophin mRNA splicing could aid treatment of the disease. Nishida et al. show that a small molecule promotes skipping of exon 31 and increases production of a functional dystrophin protein in a patient.

    • Atsushi Nishida
    • , Naoyuki Kataoka
    •  & Masafumi Matsuo
  • Article |

    The pre-mRNA splicing and TREX mRNA export machineries are found in nuclear speckle domains. Diaset al. microinject CMV-DNA constructs into cells and find that transcripts containing functional splice sites accumulate in nuclear speckles and that the TREX complex is required to release the mRNA once processed.

    • Anusha P. Dias
    • , Kobina Dufu
    •  & Robin Reed