News & Views

  • News & Views |

    The ability of CRISPR-Cas9 to accurately and efficiently target and cleave any segment of double-stranded DNA based solely on the sequence of its loaded guide RNA has revolutionized genome editing. While many structural studies have shed light on the atomic details of DNA targeting, structures of the enzyme poised to perform catalysis have remained elusive. In this issue, Zhu, Clarke, Puppala et al. provide snapshots of the enzyme in action as it performs concerted cleavage of a target DNA1.

    • David W. Taylor
  • News & Views |

    The ‘tubulin code’, a set of post-translational modifications to the microtubule cytoskeleton that include removal of the C-terminal Tyr of α-tubulin, regulates the biological function of the polymer. Three studies now report structures of VASH1–SVBP and VASH2–SVBP heterodimers and provide insights into how these proteases recognize and cleave the terminal Tyr of α-tubulin.

    • Kevin C. Slep
  • News & Views |

    Abasic sites are among the most frequent DNA lesions, and when they occur within single-stranded DNA, their repair can give rise to genomic instability and mutations. One mechanism for the protection of abasic sites involves covalent attachment of 5-hydroxymethylcytosine-binding, embryonic stem cell–specific (HMCES) protein to DNA. Now, two research groups have elucidated the structural basis of the action of HMCES and its bacterial equivalent, YedK, revealing a unique and intriguing chemistry of DNA–protein crosslink formation.

    • Marcin Nowotny
  • 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
  • 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
  • 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
  • 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
  • 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
  • News & Views |

    A new study reveals how the oocyte-specific transcription factor TAp63 ensures female germ line fidelity and describes approaches to circumvent premature ovarian insufficiency in women receiving cytotoxic chemotherapy.

    • Wa Xian
    •  & Frank McKeon
  • News & Views |

    Transcripts with highly complementary sequences can target microRNAs (miRNAs) for degradation, but the physiological relevance of target-directed miRNA degradation (TDMD) has remained unclear. Bitetti et al. now identify a conserved vertebrate RNA that induces TDMD in the cerebellum of zebrafish and mouse to promote wild-type animal behaviors.

    • Manuel de la Mata
    •  & Helge Großhans
  • News & Views |

    Chd1 is a highly conserved chromatin remodeler found across all eukaryotic species. A recent study shows the structural changes that take place when yeast Chd1 binds to its nucleosomal substrate and reveals how they relate to remodeler function.

    • Michaela M. Smolle
  • News & Views |

    The helicase intrinsic to DNA polymerase θ (Polθ), the versatile mediator of microhomology-based repair of DNA double-strand breaks and stalled replication forks, is now revealed to be a member of an elite group of proteins known as annealing helicases. This small family of enzymes remodels DNA intermediates in multiple repair processes that are crucial to preserving genome stability and warding off cancer and aging.

    • Judith L Campbell
    •  & Hongzhi Li
  • News & Views |

    The crystal structure of an oligosaccharyltransferase in complex with a sugar donor and an acceptor peptide provides insight into the mechanism of protein glycosylation and reveals how lipid-linked oligosaccharides are positioned in the enzyme active site.

    • Shiteshu Shrimal
    • , Natalia A Cherepanova
    •  & Reid Gilmore
  • News & Views |

    Deadenylation of mRNAs is generally associated with translational inhibition and mRNA decay. A study now reports that, unexpectedly, highly expressed genes tend to have shorter poly(A) tails and suggests that poly(A) tails can be 'pruned', generating a 30-nucleotide-biased phased distribution, likely due to protection by poly(A)-binding proteins.

    • Luciana A Castellano
    •  & Ariel A Bazzini
  • News & Views |

    Assembly of the small ribosomal subunit from an RNA strand and 33 proteins is an intricate and dynamic process. Two cryo-EM studies now provide insight into a complicated complex of at least 51 trans-factors that act on the preribosomal small subunit to sequentially fold it into a 3D molecular machine.

    • Joanna Rorbach
    • , Shintaro Aibara
    •  & Alexey Amunts
  • News & Views |

    C-type inactivation is a process by which ion flux through a voltage-gated K+ channel is regulated at the selectivity filter. A recent structure of the Kv1.2 channel provides a view into the structural changes of the selectivity filter during C-type inactivation.

    • Francis I Valiyaveetil
  • News & Views |

    PERK is a major sensor of the unfolded protein response controlling cell fate under endoplasmic reticulum (ER) stress. A new study reveals an additional step for optimal PERK signaling, involving the binding of CNPY2 to PERK's luminal domain. The PERK–CNPY2 axis was shown to enhance cell death under ER stress in vivo influence liver disease.

    • Hery Urra
    •  & Claudio Hetz
  • News & Views |

    PCSK9 enhances LDL cholesterol (LDL-c) levels by escorting the liver LDL receptor (LDLR) to endosomes and lysosomes for degradation. PCSK9 monoclonal antibodies and RNA-antisense formulations are effective in reducing LDL cholesterol in patients. The recent structural identification of a novel pocket in PCSK9 paves the way to the future development of orally active small-molecule hypocholesterolemic drugs.

    • Nabil G Seidah
  • News & Views |

    The cellular crosstalk between different classes of regulatory noncoding RNAs has reached a new spatial dimension. Jiang et al. reveal an essential role of a nuclear-paraspeckle-organizing long noncoding RNA and its protein partners in regulating the first steps of microRNA biogenesis.

    • Jacek Krol
  • News & Views |

    The monoallelic expression of many imprinted genes in mammals depends on DNA methylation marks that originate from the germ cells. Recent studies in mice and fruit flies evoke a novel, transient mode of genomic imprinting in which oocyte-acquired histone H3 Lys27 trimethylation (H3K27me3) marks are transmitted to the zygote and modulate the allele specificity and timing of gene expression in the early embryo.

    • Rakesh Pathak
    •  & Robert Feil
  • News & Views |

    The robustness of the circadian clock deteriorates with aging. Two new studies show that aging reprograms the circadian transcriptome in a cell-type-dependent manner and that such rewiring can be reversed by caloric restriction.

    • Rika Ohkubo
    •  & Danica Chen