News & Comment

  • News & Views |

    Viral mRNA synthesis is an essential step in the influenza virus replication cycle and is a prime target for the development of new antivirals. New structures of the influenza virus RNA polymerase now unveil previously unknown details of influenza virus transcription.

    • Aartjan J. W. te Velthuis
  • News & Views |

    Two recent cryo-EM structures of the human L-type heteromeric amino acid transporter LAT1–CD98hc reveal surprising new insights into both amino acid transport in the human body and the roles of CD98hc as a cell-surface antigen and trafficking chaperone.

    • Simon Newstead
  • News & Views |

    Epigenetic memory of silent chromatin often requires robust feedback loops between factors processing small non-coding RNAs and enzymes involved in heterochromatin assembly. A study published in Molecular Cell now demonstrates that these feedback loops can persist in a phenotypically neutral state even when gene expression is reactivated, and that they maintain the potential to reinstall heterochromatin in later generations when conditions change.

    • Matías Capella
    •  & Sigurd Braun
  • Comment |

    The long non-coding RNA Xist induces heterochromatinization of the X chromosome by recruiting repressive protein complexes to chromatin. Here we gather evidence, from the literature and from computational analyses, showing that Xist assemblies are similar in size, shape and composition to phase-separated condensates, such as paraspeckles and stress granules. Given the progressive sequestration of Xist’s binding partners during X-chromosome inactivation, we formulate the hypothesis that Xist uses phase separation to perform its function.

    • Andrea Cerase
    • , Alexandros Armaos
    • , Christoph Neumayer
    • , Philip Avner
    • , Mitchell Guttman
    •  & Gian Gaetano Tartaglia
  • News & Views |

    Cytosine methylation (m5C) is one of the more disputed base modifications of the epitranscriptome, mostly because current methods for detection are prone to artifacts. A new approach to increase detection accuracy reveals intriguing evidence of a role for the tRNA methyltransferase NSUN2 in the methylation of mRNA.

    • Lukas Trixl
    •  & Alexandra Lusser
  • News & Views |

    In the ribosome-associated quality control (RQC) pathway, stalled ribosomes are ubiquitinated and dissociated into subunits. The nascent protein chain associated with the 60S ribosomal subunit is ubiquitinated by the E3 ligase Listerin (Ltn1) and is released from tRNA by ANKZF1 (Vms1) for proteasomal degradation. Shao and colleagues now report that ANKZF1 (Vms1)-cleaved tRNAs are recycled via a two-step process that requires the removal of a terminal 2′,3′-cyclic phosphate and the addition of CCA by TRNT1.

    • Toshifumi Inada
  • News & Views |

    Ribonucleotides that are misincorporated into DNA during replication are removed by topoisomerase 1, which generates 3′-terminal adducts that are not amenable to DNA repair and thus compromise genome stability. A recent report by Li et al. reveals that Apn2/APE2 resolves such blocked 3′ termini, thereby suppressing topoisomerase 1–induced mutations at ribonucleotide monophosphate sites within the genome.

    • Shan Yan
  • News & Views |

    Bacteriophage-encoded anti-CRISPR (Acr) proteins were previously thought to inhibit CRISPR-mediated immunity by acting as physical barriers against the binding or cleavage of DNA. Two new studies report that recently discovered type V Acr proteins use enzymatic activities to shut down the Cas12a endonuclease, providing a multi-turnover ‘off switch’ for CRISPR-based immunity and technology.

    • Shravanti K. Suresh
    • , Karthik Murugan
    •  & Dipali G. Sashital
  • News & Views |

    RNAs perform diverse cellular functions that are mediated at least in part by their structure. However, how RNA structure changes throughout the RNA lifecycle and how these changes affect RNA function remain incompletely understood. A detailed in vivo characterization of RNA structure in various cellular subcompartments now provides insights into how RNA structural changes influence translation, RNA decay, protein binding and RNA modification.

    • Angela M Yu
    •  & Julius B. Lucks
  • News & Views |

    Intertwining of DNA molecules frequently results in the formation of ‘ultrafine bridges’ between sister chromatids that need to be resolved during segregation of the chromatids into daughter cells. Although it has been established that these DNA bridges are coated by the helicase PICH, it has remained unknown how PICH assists in their resolution. A study now reveals that PICH directs the formation of positive DNA supercoiling in the presence of type I topoisomerases to promote the subsequent disentanglement of these DNA helices by type II topoisomerases. Remarkably, PICH might be able to reconfigure DNA topology by extruding loops of DNA while it moves along the double helix.

    • Shveta Bisht
    •  & Christian H. Haering
  • News & Views |

    Chromatin organization in the nucleus plays an important role in cell-type-specific gene expression. A new study reports reconstruction of the 3D genome in single sensory neurons and provides insights into the regulation of genes encoding odorant receptors.

    • Lúcia M. Armelin-Correa
    •  & Bettina Malnic
  • News & Views |

    Ubiquitin and ubiquitin-like proteins (UBLs) are essential regulators of a multitude of cellular processes, including autophagy. It is known that these proteins relay their effects by covalently modifying their substrate molecules. As an exception to this norm, Pang et al. report a novel phenomenon in which the UBL ATG12 interacts with its substrate ATG5 in a non-covalent fashion to promote autophagy in apicomplexan parasites and some yeasts.

    • Varnesh Tiku
    •  & Ivan Dikic
  • News & Views |

    Last year, several studies reported that proteins form biomolecular condensates at gene enhancers. Nair et al. now show that these condensates undergo physical changes over time, which affects their nuclear localization and the transcriptional output of their target genes.

    • Sina Wittmann
    •  & Simon Alberti
  • News & Views |

    Autophagy is a highly contextual modulator of tumorigenesis. A new study shows that autophagy can serve as a tumor suppressor to mediate cell death at replicative crisis.

    • Masashi Narita
  • News & Views |

    Structural information on the respiratory supercomplex III2IV2 from budding yeast and from Mycobacterium smegmatis has become available, with cryo-EM work from four different groups.

    • Joana S. Sousa
    •  & Janet Vonck
  • News & Views |

    A growing body of evidence suggests that cotranslational folding occurs from bacteria to mammalian cells, in particular for multi-domain proteins. In the assembly of yeast proteasomes, the initial interaction of Rpt1 and Rpt2 subunits has been found to take place on the translating ribosomes, coordinated by elongation pausing and involving the formation of Not1-containing compartments.

    • Xiao-Min Liu
    •  & Shu-Bing Qian
  • Meeting Report |

    The Ninth International Conference on the Hsp90 Chaperone Machine concluded in October 2018, in Leysin, Switzerland. The program highlighted findings in various areas, including integrated insights into the molecular mechanism of Hsp90, cochaperones, and clients’ structure and function.

    • Laura J. Blair
    • , Olivier Genest
    •  & Mehdi Mollapour
  • News & Views |

    The intertwined structure of the Taf5–Taf6–Taf9 subcomplex is dependent on the chaperonin CCT for its assembly and subsequent integration into the general transcription factor TFIID.

    • Alan C. M. Cheung
  • News & Views |

    Recent advances in the ability to detect mRNA base modifications have led to a renewed appreciation for the diversity of the epitranscriptome and its ability to influence gene expression. Now, a study in Cell adds acetylated cytidine (ac4C) to the list, identifying it as a widespread mark in cellular mRNAs that influences both mRNA stability and translation.

    • Seung H. Choi
    •  & Kate D. Meyer
  • News & Views |

    Attempts to develop a method for 3D genome reconstruction of single cells have been frustrated by the inability to distinguish between chromosome homologs. A novel Hi-C workflow uses haplotype imputation to map the nuclear organization of single diploid cells.

    • Blake A. Caldwell
    •  & Marisa S. Bartolomei
  • Meeting Report |

    Cells rely on the synthesis, translocation, folding and turnover of proteins. Owing to complexity, spatiotemporal regulation and surveillance of these processes are vital. Advances in the field were discussed at the international symposium ‘Proteins: From the Cradle to the Grave’ that took place in the wonderful setting of a Buddhist temple located close to Kyoto, Japan. The emerging theme was the interdependence among cellular processes and organelle compartments.

    • Johannes M. Herrmann
    • , Pedro Carvalho
    • , Manajit Hayer-Hartl
    •  & Tohru Yoshihisa
  • News & Views |

    The σ1 receptor, an endoplasmic reticulum–resident transmembrane protein, modulates many physiological and pathological processes and binds multiple drugs, but is nonetheless poorly understood. In a recent issue, Kruse and colleagues illustrate structural differences between agonist- and antagonist-bound receptor and propose that agonist binding may impair oligomerization, making a major step in understanding σ1 function. They also use a combination of kinetic and molecular dynamic modeling to explain how ligands access the binding pocket.

    • Felix J. Kim
    •  & Gavril W. Pasternak
  • News & Views |

    RNA uridylation offers a basis for diverse post-transcriptional regulation. Two recent studies reveal new roles of uridylation in immune defense against viruses and retrotransposons.

    • Jinah Yeo
    •  & V. Narry Kim
  • Meeting Report |

    A symposium in June 2018 sponsored by the Center on Membrane Protein Production and Analysis, a unit of the New York Structural Biology Center, focused on the structures of proteins residing in biological membranes. Explicit emphasis was placed on currently developing technologies aimed at determining such structures and at understanding their dynamics, mechanisms and complex interactions.

    • Chris Miller
  • News & Views |

    The effects of RNA secondary structure on translation have been well recognized; however, the global interplay between both in a dynamic cellular system is poorly understood. Beaudoin, Giraldez and colleagues have analyzed RNA structure dynamics during zebrafish embryonic development and have found that the ribosome unzips mRNA secondary structure during translation, thus leading to a global decrease of structure in highly translated transcripts. Furthermore, the authors establish RNA structure in the 3′ untranslated regions of mRNAs as a major regulator of transcript stability in this context.

    • Marianne C. Kramer
    •  & Brian D. Gregory
  • News & Views |

    The mechanism underlying CCG-repeat expansions in patients with fragile X premutation is not well understood. Using a new experimental system in mammalian cells, a study in this issue reports that break-induced replication has a role in CGG-repeat instability.

    • Madhura Deshpande
    •  & Jeannine Gerhardt
  • News & Views |

    A series of new cryo-EM structures reveals a surprising twist in how the RAG complex initiates V(D)J recombination. The initial complex with substrate DNA adopts two conformations: in one, the DNA is relatively undistorted but the scissile phosphate is far from the active site, and in the other the DNA is partially melted and unwound by half a turn, which allows the scissile phosphate to dock into the active site. Similar pre-catalysis DNA melting may occur with other DDE recombinases, for which equivalent complexes with uncleaved substrate DNA are not yet available.

    • Fred Dyda
    •  & Phoebe A. Rice
  • News & Views |

    Under steady-state conditions, the E3 ubiquitin ligase Parkin is localized to the cytosol in an autoinhibited state. Two recent studies describe the mechanism of Parkin activation by phosphorylation via structural rearrangement of the Ubl and RING2 domains, explaining how the RING2 domain is released from the core of Parkin to allow for ubiquitination of its substrates.

    • François Le Guerroué
    •  & Richard J. Youle
  • News & Views |

    In a stress-free environment, the histone binding function of 53BP1 is inhibited by TIRR, but upon DNA damage 53BP1 is recruited to chromatin and promotes DNA repair. New structural studies provide insights into the mechanisms underlying 53BP1 inhibition and activation. TIRR physically blocks the methyl-lysine histone-binding site of Tudors, and RNA binding by TIRR alleviates this block.

    • Yi Zhang
    •  & Tatiana G. Kutateladze
  • News & Views |

    Activation signals from GPCRs, the largest receptor family, are transmitted to heterotrimeric G proteins and arrestins, and can be differentially modulated by GPCR phosphorylation. In a recent article, available data, including multiple arrestin structures, are analyzed to decipher common and state-specific conformational changes in arrestins and how these depend on patterns of receptor phosphorylation.

    • Christopher J. Draper-Joyce
    •  & Arthur Christopoulos
  • News & Views |

    Traditional approaches to covalent drug design postulate that noncovalent binding affinity (Ki) should be in the nanomolar range for the lead compound to be attractive. A study by Hansen et al. suggests that covalent K-Ras inhibitors can have weak noncovalent binding affinity yet have fast chemical reactivity (kinact), because K-Ras enhances the covalent reactivity of bound inhibitor, similarly to how enzymes activate their substrates.

    • Alexander V. Statsyuk
  • News & Views |

    Recent developments in transcriptome-wide sequencing technologies have enabled the identification of cellular mRNA decay intermediates. Although canonical mRNA decay has been shown to occur by deadenylation followed by decapping and subsequent exonucleolytic decay from both mRNA ends, a study by Mourelatos and colleagues now defines mRNA fragments that are generated on polysomes by endonucleolytic cleavages phased by the associated ribosome.

    • Tatsuaki Kurosaki
    •  & Lynne E. Maquat
  • News & Views |

    Nanobodies have emerged as highly versatile and useful binding molecules in biomedical research. A technical report describes a cost- and time-effective in vitro platform that facilitates the generation of desired nanobodies, including conformationally selective nanobodies against agonist-bound G-protein-coupled receptors (GPCRs).

    • Ulrich Rothbauer
  • News & Views |

    Inheritance of Polycomb repressive complex 2 (PRC2)-mediated gene silencing involves self-propagation of histone H3 lysine 27 (H3K27) methylation from an initial nucleation site, but how the first H3K27 methylation marks are established is not fully understood. A recent study reveals that PRC2 can reconstitute H3K27 methylation de novo in cells that have lost the mark. This reconstitution is dependent on the PRC2 core component SUZ12, which provides a novel link between initiation and self-propagation of this critical epigenetic mark.

    • Jafar Sharif
    •  & Haruhiko Koseki