Molecular biology

  • Article
    | Open Access

    Polycomb (PcG) proteins are known to promote cell proliferation by silencing expression of the tumour suppressor Ink4A-Arf. Piunti et al.show that PcG proteins also regulate tumour progression independently of this role, revealing a requirement for PRC1 and PRC2 in replication fork progression.

    • Andrea Piunti
    • , Alessandra Rossi
    •  & Diego Pasini
  • Article
    | Open Access

    microRNAs regulate gene expression and control cell fate and differentiation processes. In this work, Nowak et al. reveal that brain-specific miR-9 is under post-transcriptional control and that the pre-miR-9 binding protein Lin28a decreases the levels of mature miR-9 during retinoic acid-mediated neuronal differentiation.

    • Jakub S. Nowak
    • , Nila Roy Choudhury
    •  & Gracjan Michlewski
  • 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 |

    Lactate racemase is an enzyme that interconverts the L and D isomers of the common metabolite lactate. Here, the authors show that lactate racemase represents a new type of nickel-dependent enzyme, which is activated by accessory proteins that are widespread among prokaryotic microbes.

    • Benoît Desguin
    • , Philippe Goffin
    •  & Pascal Hols
  • Article |

    Cell cycle regulation of the two major DNA double-strand break repair pathways—NHEJ and HR—is critical for the maintenance of genome integrity. Here, Tomimatsu et al. show that phosphorylation of the nuclease EXO1 by cyclin-dependent kinases affects repair pathway choice by controlling long-range resection.

    • Nozomi Tomimatsu
    • , Bipasha Mukherjee
    •  & Sandeep Burma
  • Article
    | Open Access

    Defective proteins or functional proteins that are no longer needed can be degraded in the endoplasmic reticulum. In this study, Lopez-Serra et al.show that DERL3, which is involved in protein degradation in the endoplasmic reticulum, is aberrantly silenced in cancer, leading to activation of a glucose transporter and dysregulated glycolysis.

    • Paula Lopez-Serra
    • , Miguel Marcilla
    •  & Manel Esteller
  • Article
    | Open Access

    CD8 expression levels on peripheral CD8+ T cells are regulated during development and effector differentiation. Here, the authors show that methylation patterns at the Cd8a locus, whose product is essential for surface CD8 expression, can change during T-cell development, activation, cytokine polarization and reprogramming.

    • Kim L. Harland
    • , E. Bridie Day
    •  & Anne Kelso
  • Article |

    Axon growth requires exocyst-dependent membrane expansion, however it is unclear how this process is spatially regulated. Gracias et al.show that axonal translation of the exocyst regulator TC10 is necessary for stimulated membrane growth, and propose that local translation coordinates membrane and cytoskeletal enlargement.

    • Neilia G. Gracias
    • , Nicole J. Shirkey-Son
    •  & Ulrich Hengst
  • Article
    | Open Access

    Cyclin-dependent kinase 12 (Cdk12) phosphorylates the C-terminal domain (CTD) of RNA polymerase II to regulate transcription. Here, the authors solve the crystal structure of the Cdk12 kinase domain and show that Cdk12 has its highest activity on a CTD substrate that carries a serine 7 phosphorylation.

    • Christian A. Bösken
    • , Lucas Farnung
    •  & Matthias Geyer
  • Article |

    Our understanding of ribosome biogenesis is limited by a lack of structural knowledge of assembly intermediates. Here, Leidig et al.report a high-resolution cryo-EM structure of a pre-60S particle that suggests that substantial rearrangements of the 5S RNP are required during ribosome maturation.

    • Christoph Leidig
    • , Matthias Thoms
    •  & Roland Beckmann
  • Article |

    Short interfering siRNAs—siRNAs—have therapeutic potential in the treatment of disease; however, their delivery to target tissues is difficult. Here, Wu et al. chemically modify siRNAs and show that this improves loading into the siRNA silencing machinery and thus efficacy in eliminating cancer cells in mice.

    • Sherry Y. Wu
    • , Xianbin Yang
    •  & Anil K. Sood
  • Article
    | Open Access

    Bacterial RNA polymerase (RNAP) is crucial for cellular gene expression and a validated target for antimicrobial drugs. Here, Malinen et al. explore the effects of the CBR class of RNAP inhibitors on the E. coliRNAP transcription cycle and provide detailed mechanistic insight into their antibacterial action.

    • Anssi M. Malinen
    • , Monali NandyMazumdar
    •  & Georgiy A Belogurov
  • Article |

    DNA replication requires re-establishment of chromatin structure, which involves incorporation of newly synthesized histones. Here, Klimovskaia et al.show that phosphorylation of the histone chaperone Asf1 by Tousled-Like Kinase stimulates its ability to bind histones, thus promoting chromatin assembly.

    • Ilnaz M. Klimovskaia
    • , Clifford Young
    •  & Anja Groth
  • Article |

    Cardiomyocyte cell cycle arrest is important for mammalian heart maturation, but the process is poorly understood. Here, the authors use exome sequencing to identify compound heterozygous ALMS1mutations associated with cardiomyocyte replication and provide evidence that Alström protein deficiency impairs postnatal cardiomyocyte cell cycle arrest.

    • Lincoln T. Shenje
    • , Peter Andersen
    •  & Daniel P. Judge
  • 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 |

    Lipoproteins such as HDL can bind and transport microRNAs throughout the body. Here the authors provide a new mechanism contributing to the anti-inflammatory effects of HDL by which HDL-associated miR-223 is transferred to endothelial cells, where it inhibits expression of the adhesion molecule ICAM-1.

    • Fatiha Tabet
    • , Kasey C. Vickers
    •  & Kerry-Anne Rye
  • Article |

    Alternative last exons (ALEs) are typically poorly conserved and excluded during splicing. Dutertre et al.identify a class of highly expressed ALEs that correspond to ancestral last exons of genes, including cell cycle genes, and are repressed by doxorubicin, in part through the HuR protein.

    • Martin Dutertre
    • , Fatima Zahra Chakrama
    •  & Didier Auboeuf
  • Article
    | Open Access

    The role of ATM in DNA double-strand break (DSB) signalling is well established, but its function in the repair process remains controversial. Here, Álvarez-Quilón et al.show that ATM acts in the joining of blocked DSBs, uncovering DNA end structure as a key factor determining ATM involvement in DSB repair.

    • Alejandro Álvarez-Quilón
    • , Almudena Serrano-Benítez
    •  & Felipe Cortés-Ledesma
  • Article |

    MicroRNA has been identified to play a role in cancer development, thus its detection at low concentrations would be a highly beneficial diagnostic tool. Here, the authors develop a gel-based bio-barcode assay for microRNA detection using DNA-modified gold nanoparticles, with aM limits of detection.

    • Hyojin Lee
    • , Jeong-Eun Park
    •  & Jwa-Min Nam
  • Article |

    Defects in the homologous recombination repair of DNA can result in gene mutation and cancer. In this study, Peng et al.identify a gene signature associated with homologous recombination repair deficiency and show that this can be used both to predict repair defects and clinical outcome in cancer patients.

    • Guang Peng
    • , Curtis Chun-Jen Lin
    •  & Shiaw-Yih Lin
  • Article |

    Bacterial two-component systems relay extracellular signals to transcriptional networks via response regulators. Narayanan et al.present structures of the response regulator KdpE bound to DNA, and show that asymmetric interactions between the receiver and DNA-binding domains are required to sustain gene expression.

    • Anoop Narayanan
    • , Shivesh Kumar
    •  & Dinesh A. Yernool
  • Article
    | Open Access

    The E3 ubiquitin ligase RNF168 ubiquitinates specific lysines on histone H2A as part of the DNA damage response. Here, the authors show that the acidic patch on the histone H2A/H2B dimer catalyses RNF168-dependent ubiquitination of histone 2A by redirecting ubiquitination activity towards the relevant target lysines.

    • Francesca Mattiroli
    • , Michael Uckelmann
    •  & Titia K. Sixma
  • Article
    | Open Access

    Gene expression is highly variable between tissues, and changes during development and with age. Here, the authors provide a comprehensive RNA-Seq analysis of the rat transcriptome, spanning eleven organs, four developmental stages and both sexes.

    • Ying Yu
    • , James C. Fuscoe
    •  & Charles Wang
  • Article |

    The forkhead box transcription factor Foxo1 is required for the maintenance of pluripotency in human embryonic stem cells. Here Koga et al.show that expression of another forkhead box transcription factor, Foxd1, promotes and indicates successful reprogramming of mouse embryonic fibroblasts.

    • Makito Koga
    • , Mitsuhiro Matsuda
    •  & Miki Ebisuya
  • Article |

    STIM proteins are key regulators of intracellular Ca2+ signalling. Here, Wang et al. demonstrate that subtle differences between STIM1 and its close homologue STIM2 have profound consequences for their ability to gate Orai1 Ca2+channels, thus revealing the basis for their distinct physiological functions.

    • Xizhuo Wang
    • , Youjun Wang
    •  & Donald L Gill
  • Article |

    Polycomb group proteins are epigenetic gene silencers that are thought to exist in two biochemically distinct multiprotein complexes, termed PRC-1 and -2. Here, Cao et al.show that EED, a core component of PRC2, interacts with and functions as part of PRC1, thus coordinating the activities of both complexes.

    • Qi Cao
    • , Xiaoju Wang
    •  & Arul M. Chinnaiyan
  • 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 |

    Glycosylation is an essential process for preservation of protein structure and biological activity. Here, the authors show that the introduction of charge clusters containing specific amino-acid sequences can instead be used to control the stability and activity of non-glycosylated proteins.

    • Nikki Y. Tan
    • , Ulla-Maja Bailey
    •  & Benjamin L. Schulz
  • Article |

    Tetraploid cotton contains two homoeologous genes GhMYB2A and GhMYB2D but their regulation is unclear. Here, GhMYB2D is shown to accumulate to higher levels than GhMYB2Aduring fibre initiation, and is a target of two microRNAs, generating ta-siRNAs, suggesting a role for microRNAs in the divergence of duplicate genes and fibre trait.

    • Xueying Guan
    • , Mingxiong Pang
    •  & Z. Jeffrey Chen
  • Article |

    Genetically engineered mice are an important aspect of human disease research. Here, the authors use artificial transcription activator-like effector-nucleases to generate a mouse line with a conditionally targeted allele and suggest that this method can be easily adapted to any gene in the mouse genome.

    • Daniel Sommer
    • , Annika E. Peters
    •  & Marc Beyer
  • 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
    | Open Access

    Non-coding RNAs have recently emerged as crucial regulators of gene expression. Here Rutnam et al.identify a pseudogene complementary to the 3′-UTR of the TUSC2 tumour suppressor that regulates TUSC2 levels by acting as a decoy for endogenous microRNAs and thereby inhibits tumorigenesis.

    • Zina Jeyapalan Rutnam
    • , William W. Du
    •  & Burton B. Yang