RNA articles within Nature Chemistry

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  • Article |

    RNA localization is key to regulating cellular function but is challenging to measure in an unbiased manner. Now a combination of enol-masked acylating probes with a bioorthogonal esterase to locally unmask them provides a non-radical RNA proximity labelling platform—termed BAP-seq—that enables the generation of high-resolution spatial maps of RNA.

    • Shubhashree Pani
    • , Tian Qiu
    •  & Bryan C. Dickinson

  • Article
    | Open Access

    The underlying mechanism for how heterotypic protein–RNA interactions modulate the liquid to amyloid transition of hnRNPA1A, a protein involved in amyotrophic lateral sclerosis, has so far remained elusive. Now characterization of hnRNPA1A condensate formation and aggregation in vitro reveals that the RNA/protein stoichiometry affects the molecular pathways leading to amyloid formation.

    • Chiara Morelli
    • , Lenka Faltova
    •  & Paolo Arosio

  • Article |

    The physicochemical driving forces of protein-free, RNA-driven phase transitions were previously unclear, but it is now shown that RNAs undergo entropically driven liquid–liquid phase separation upon heating in the presence of magnesium ions. In the condensed phase, RNAs can undergo an enthalpically favourable percolation transition that leads to arrested condensates.

    • Gable M. Wadsworth
    • , Walter J. Zahurancik
    •  & Priya R. Banerjee

  • News & Views |

    Site-specific modification of RNA in cells is crucial for analysis and functional investigations. Natural enzymes that promote RNA methylation using S-adenosyl-l-methionine (SAM) exist, but leveraging these proteins for RNA modification is limited by cell permeability, stability and specificity of their substrates. Now, a de novo ribozyme that acts on a stabilized and cell-permeable SAM analogue enables site-specific RNA modification with a click handle in living cells.

    • Nicolas V. Cornelissen
    •  & Andrea Rentmeister

  • News & Views |

    Medicinal chemistry efforts typically focus on drug–protein interactions and overlook RNA binding as a source of off-target pharmacology. Now, a new method has been developed to map the interactions of small-molecule drugs with RNA in cells and characterize how these interactions can exert functional effects.

    • Christopher R. Fullenkamp
    •  & John S. Schneekloth Jr

  • Article
    | Open Access

    Ribozyme-mediated post-transcriptional RNA modification is a powerful method for site-specific RNA labelling and analysis of RNA functions. Now, an alkyltransferase ribozyme—termed SAMURI—has been shown to catalyse the transfer of a propargyl group from a stabilized synthetic S-adenosylmethionine analogue to a specific adenosine on the target RNA within cells.

    • Takumi Okuda
    • , Ann-Kathrin Lenz
    •  & Claudia Höbartner

  • Article |

    Now a reactivity-based RNA profiling strategy can measure the global off-target transcriptome interactions of small-molecule drugs at single-nucleotide resolution. Using this approach, three FDA-approved drugs were evaluated, uncovering pervasive drug–RNA interactions and interactions that perturb RNA functions in cells.

    • Linglan Fang
    • , Willem A. Velema
    •  & Eric T. Kool

  • Article |

    Stabilization of RNAs for storage, transport and biological application remains a profound challenge. Now, it has been shown that reversible 2′-OH acylation with easily accessible acylimidazoles unlocks efficient protection of RNA. RNA can be deprotected by non-basic nucleophiles or spontaneously in cells to restore RNA functions.

    • Linglan Fang
    • , Lu Xiao
    •  & Eric T. Kool

  • News & Views |

    Interactions between proteins and non-proteinaceous biopolymers are essential for life; however, many methods used to characterize these interactions lack precision and display significant biases. Now, a genetically encoded method employing sulfur(vi) fluoride exchange (SuFEx)-based chemical crosslinking has been developed for capturing and analysing protein–RNA and protein–carbohydrate interactions in vivo.

    • Christopher P. Watkins
    •  & Ryan A. Flynn

  • Article |

    Synthesis of peptidyl-tRNAs is challenging because there are no enzymes that can directly attach the desired peptide to tRNA. Now it has been shown that a chemoenzymatic approach based on native chemical ligation can be used for the semi-synthesis of peptidyl-tRNAs for structural/biochemical studies of arrested and non-arrested ribosome complexes.

    • Egor A. Syroegin
    • , Elena V. Aleksandrova
    •  & Yury S. Polikanov

  • News & Views |

    DNA nanotechnology and synthetic biology both aim to expand the range of dynamic behaviours exhibited by rationally programmed biomolecules. Now, the programmability of synthetic transcriptional circuits has been improved to enable synthesis of dynamic biomolecular circuits with unmatched complexity.

    • Jongmin Kim
    •  & Friedrich C. Simmel

  • Article |

    Protein–RNA interactions regulate RNA fate and function, and are generally non-covalent and reversible. Genetically introducing a latent bioreactive amino acid into a protein is now shown to enable the protein to covalently crosslink a bound RNA molecule in vivo. This method offers innovative avenues for developing protein–RNA research and applications.

    • Wei Sun
    • , Nanxi Wang
    •  & Lei Wang

  • Article
    | Open Access

    Analogues of mRNA 5′ caps containing a photo-cleavable group have now been developed. These so-called FlashCaps can be used for routine in vitro transcription to make long mRNAs containing a cap. In cells, the capped mRNAs are translationally muted; however, upon irradiation by light, the photo-cleavable group is removed without leaving any remaining modification and mRNA is then translated into the corresponding protein.

    • Nils Klöcker
    • , Florian P. Weissenboeck
    •  & Andrea Rentmeister

  • Article |

    The correct function of ribozymes in a prebiotic world would be dependent on the presence of optimal salt compositions and concentrations. Now, local heat fluxes have been shown to create an ideal salt habitat for ribozyme activity based on geologically plausible salt-leaching processes.

    • T. Matreux
    • , K. Le Vay
    •  & C. B. Mast

  • Article |

    Elucidating the origin of translation—the process that produces a specific peptide from an RNA sequence—is one of the most difficult challenges in prebiotic chemistry and evolutionary biology. Now, it has been shown that aminoacylated nucleotides couple to amino-acid-bearing oligoribonucleotides, directed by an RNA template, forming specific di- and tripeptides in the absence of ribosomal machinery.

    • Biswarup Jash
    • , Peter Tremmel
    •  & Clemens Richert

  • News & Views |

    Nucleic acids can adopt G-quadruplex folds whose cellular roles remain poorly defined. Synthesis of new probes has now enabled the identification of human proteins that interact with G-quadruplexes. This could provide new clues to decipher the function of these curious folds.

    • Aaron M. Fleming
    •  & Cynthia J. Burrows

  • Article |

    A selection-based screen has now revealed preferences in small-molecule chemotypes that bind RNA as well as preferences in the RNA motifs that bind small molecules. Analysis of these data enabled the design of a small molecule that selectively binds a non-coding microRNA and upregulates expression of vascular endothelial growth factor A.

    • Hafeez S. Haniff
    • , Laurent Knerr
    •  & Matthew D. Disney

  • Article |

    The Varkud satellite ribozyme, which catalyses site-specific RNA cleavage and ligation, is an important model to understand RNA catalysis. Now, a combination of theoretical and experimental work has revealed new details about its catalytic mechanism. Mg2+ is shown to play an important role in organizing the active site, and the proton transfers in the transition state have also been identified.

    • Abir Ganguly
    • , Benjamin P. Weissman
    •  & Darrin M. York

  • Article |

    The emergence of pristine RNA and DNA on the early Earth would have been hindered by a lack of specificity in their prebiotic syntheses. Now, it has been shown that chimeric sequences—with a mixture of RNA and DNA backbones—mediate the template-directed ligation of oligomers present in mixtures of nucleic acids, enabling the simultaneous appearance of RNA and DNA.

    • Subhendu Bhowmik
    •  & Ramanarayanan Krishnamurthy

  • Article |

    RNA is usually considered to be the first genetic polymer, with DNA a product of a biochemical pathway that arose after the origin of life. Now, studies into the prebiotic phosphorylation of an RNA nucleoside reveal pathways for the synthesis of DNA building blocks, providing experimental support for a prebiotic link between RNA and DNA.

    • Jianfeng Xu
    • , Nicholas J. Green
    •  & John D. Sutherland

  • Article |

    Lysine-rich peptides from the ribosomal core and derived homolysine decapeptides of either L-, D- or mixed chirality have now been shown to enhance RNA polymerase ribozyme activity at low magnesium concentrations, accelerate ribozyme evolution and enable templated RNA synthesis within membranous protocells.

    • Shunsuke Tagami
    • , James Attwater
    •  & Philipp Holliger

  • Article |

    Identifying a non-enzymatic method of replicating RNA for multiple cycles has been problematic because rapid strand reannealing outcompetes slow non-enzymatic template copying. Now, oligoarginine peptides have been shown to inhibit reannealing while still allowing short primers and activated monomers to bind to the template strand, facilitating the next round of template copying.

    • Tony Z. Jia
    • , Albert C. Fahrenbach
    •  & Jack W. Szostak

  • News & Views |

    The low-complexity-protein, liquid phases of membraneless organelles have now been established to selectively partition biomolecules. The specialized microenvironment that they provide differs chemically from the surrounding medium and enables specific nucleic-acid remodelling reactions.

    • James Shorter

  • Article |

    The development of cells requires a mechanism to support homeostasis—the maintenance of constant internal conditions—as cellular growth results in internal dilution. Now, a simple physical process is described in which short oligonucleotide inhibitors enable dilution-driven activation of encapsulated ribozymes via membrane growth, suggesting homeostatic mechanisms could have existed in the earliest cells.

    • Aaron E. Engelhart
    • , Katarzyna P. Adamala
    •  & Jack W. Szostak

  • Article |

    The repertoire of amino acids available for ribosomal peptide synthesis is limited by the genetic code. Now, a method to reduce the redundancy of codons has been developed based on the artificial division of codon boxes. This method enables non-proteinogenic amino acids to be included in peptides without sacrificing proteinogenic ones.

    • Yoshihiko Iwane
    • , Azusa Hitomi
    •  & Hiroaki Suga

  • Article |

    Intracellular bodies called liquid organelles are rich in nucleic acids and proteins, and are thought to occur by liquid–liquid phase coexistence. Now, enzymatic control over the phosphorylation state of a simple cationic peptide, thereby altering its electrostatic interaction with RNA, has been shown to drive formation and dissolution of droplets that mimic these intracellular liquid bodies.

    • William M. Aumiller Jr
    •  & Christine D. Keating

  • Article |

    The question of how divalent metal ions direct the folding of ribozymes is a major unsolved problem. A computational model has now been used to reveal the molecular mechanism by which Mg2+ drives the Azoarcus ribozyme into a catalytically functional state. Simulations also show that although Ca2+ drives folding it leaves the active site unstable.

    • Natalia A. Denesyuk
    •  & D. Thirumalai

  • Article |

    During the early stages of life on Earth sophisticated RNA catalysts must have formed from simple precursors. Here it is shown that freeze–thaw cycles can drive the assembly of complex RNA polymerase ribozymes from networks of short RNA oligonucleotides through an unanticipated RNA chaperone effect.

    • Hannes Mutschler
    • , Aniela Wochner
    •  & Philipp Holliger

  • News & Views |

    An RNA replicase ribozyme has long been sought by chemists interested in the origin of life. Now, a selection strategy employing a low-temperature water–ice mixture as the medium has led to discovery of a ribozyme that can catalyse polymerization of an RNA chain greater than its own length.

    • Niles Lehman

  • News & Views |

    Selection of an RNA catalyst that can use the vitamin thiamin to catalyse a key metabolic decarboxylation reaction has broad implications for understanding the role of RNA in the early stages of chemical evolution.

    • Cynthia J. Burrows

  • Article |

    Molecular self-replication through ribozyme-catalysed RNA synthesis could shed light on the origins of life. Here, a polymerase ribozyme capable of synthesizing an RNA sequence longer than itself is described, based on a cold-adapted ribozyme variant evolved in ice. This process demonstrates the potential for the emergence of novel ribozyme phenotypes in altered reaction environments.

    • James Attwater
    • , Aniela Wochner
    •  & Philipp Holliger

  • Article |

    Vitamins are thought to be relics of a primordial RNA World. A demonstration that catalytic RNAs are capable of harnessing vitamin cofactors would support the likely role of vitamins in early metabolic processes. Here, a ribozyme that uses vitamin B1 to aid decarboxylation of a pyruvate-like substrate is reported.

    • Paul Cernak
    •  & Dipankar Sen

  • News & Views |

    Non-enzymatic copying of an RNA template is appealing as a transition from pre-life to an RNA world, but it has been difficult to demonstrate in the laboratory. Now, two separate studies focusing on RNA's backbone connectivity offer partial solutions to some of the problems raised with this hypothesis for the origin of life.

    • Armando R. Hernández
    •  & Joseph A. Piccirilli

  • Article |

    An RNA aptamer and a ribozyme are both observed to retain a surprising degree of activity despite backbone heterogeneity caused by the presence of non-natural 2′–5′ phosphodiester linkages. These results suggest that absolute regioselectivity of non-enzymatic replication may not have been required for the emergence of RNA as the first biopolymer.

    • Aaron E. Engelhart
    • , Matthew W. Powner
    •  & Jack W. Szostak

  • Article |

    One theory for the abiogenesis of RNA involves ligation of shorter oligomers that are observed after dry-state condensation of mononucleotides. Here, the chemo- and regioselective acetylation of (oligo)nucleotides in water under prebiotically plausible conditions is described. This remarkable selectivity permits the rapid template-directed ligation of oligomers to favour extant 3′,5′-linkages.

    • Frank R. Bowler
    • , Christopher K. W. Chan
    •  & Jianfeng Xu

  • Article |

    RNA compartmentalization is essential for cellular functions and may have played a pivotal role in the emergence of life. However, the consequences of compartmentalization on RNA catalysis have been largely unexplored. Here, partitioning of catalytic RNA in a two-phase aqueous polymer solution increased local RNA concentration, enhancing ribozyme kinetics.

    • Christopher A. Strulson
    • , Rosalynn C. Molden
    •  & Philip C. Bevilacqua

  • Article |

    The pre-RNA-world hypothesis postulates that RNA was preceded in the evolution of life by a simpler genetic material. Here, Darwinian evolution methods were used to generate a threose nucleic acid (TNA) aptamer. This result provides evidence that TNA could have served as an ancestral genetic system during an early stage of life.

    • Hanyang Yu
    • , Su Zhang
    •  & John C. Chaput

  • News & Views |

    Mutating RNA one nucleotide at a time and measuring the impact of this on its chemical reactivity provides a strategy for determining its three-dimensional structure, and from there, hopefully, its function.

    • Katja Petzold
    •  & Hashim M. Al-Hashimi

  • Article |

    A drawback of recently reported prebiotic routes to RNA is a requirement for enantioenriched reactants. Here, the presence of a slightly enantioenriched amino acid in the reaction mixture is shown to drive the formation of enantiopure RNA precursors. This provides a plausible scenario in which single-handed biological molecules were formed prior to the emergence of self-replicating informational polymers.

    • Jason E. Hein
    • , Eric Tse
    •  & Donna G. Blackmond

  • Article |

    A long-standing problem with the RNA-world hypothesis is that enzyme-free replication of RNA strands has not been demonstrated. Here, immobilization of a template strand and periodic replacement of a solution containing activated nucleotides allows the copying of unmodified RNA sequences containing any of the four natural nucleobases in near-quantitative yield.

    • Christopher Deck
    • , Mario Jauker
    •  & Clemens Richert

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