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| Open AccessTermination of the unfolded protein response is guided by ER stress-induced HAC1 mRNA nuclear retention
Chromatin remodeler Isw1 prevents export of maturing ribonucleoprotein particles. Here, the authors show that Isw1 inhibits the Unfolded Protein Response (UPR) from the nucleus by binding and restricting export of the mRNA encoding the main effector of UPR, thereby tuning adaptation to ER stress.
- Laura Matabishi-Bibi
- , Drice Challal
- & Anna Babour
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Article
| Open AccessSplicing factor BUD31 promotes ovarian cancer progression through sustaining the expression of anti-apoptotic BCL2L12
Altered expression of splicing factors can contribute to tumour progression. Here the authors show that splicing factor BUD31 enhances ovarian cancer progression by promoting exon inclusion in the anti-apoptotic BCL2 family member, BCL2L12.
- Zixiang Wang
- , Shourong Wang
- & Zhaojian Liu
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Article
| Open AccessSequential action of a tRNA base editor in conversion of cytidine to pseudouridine
C-to-Ψ conversion is a previously uncharacterized form of base editing. Here, the authors describe how the TrcP enzyme catalyzes this process in a stepwise fashion and how this editing process is controlled by a network of modifications and nutrient availability to optimize translation efficiency.
- Satoshi Kimura
- , Veerasak Srisuknimit
- & Matthew K. Waldor
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Article
| Open AccessThe solution structure of Dead End bound to AU-rich RNA reveals an unusual mode of tandem RRM-RNA recognition required for mRNA regulation
The authors report an unusual mode of AU-rich RNA recognition by the RNA recognition motifs of DND1, a protein essential for germline development, in a 27.5 kDa NMR structure and provide additional insight on DND1 function from cell-based experiments.
- Malgorzata M. Duszczyk
- , Harry Wischnewski
- & Frédéric H.-T. Allain
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Article
| Open AccessStructural basis for Gemin5 decamer-mediated mRNA binding
Structural biology, complemented by biochemistry experiments and RNA-binding assays show that the Gemin5 C-terminal region adopts a decamer architecture. Gemin5 decamerization is essential for its role in regulating mRNA translation.
- Qiong Guo
- , Shidong Zhao
- & Chao Xu
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Article
| Open AccessDuplicated ribosomal protein paralogs promote alternative translation and drug resistance
Most yeast ribosomal protein genes are duplicated but the functional significance of this duplication remains unclear. This study identifies a natural program where changing the ratio of proteins produced from duplicated genes modifies translation in response to drugs regardless of ribosome number.
- Mustafa Malik Ghulam
- , Mathieu Catala
- & Sherif Abou Elela
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Article
| Open AccessExperimental exploration of a ribozyme neutral network using evolutionary algorithm and deep learning
Neutral networks, which are sets of genotypes connected via single mutations that share the same phenotype, are important for evolvability. Here, the authors provide experimental evidence of a neutral network in an RNA enzyme using a high-throughput assay and deep learning.
- Rachapun Rotrattanadumrong
- & Yohei Yokobayashi
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Article
| Open AccessStructural and biochemical basis for DNA and RNA catalysis by human Topoisomerase 3β
The authors revealed novel roles of catalytic residues and divalent metal ions for hsTOP3B, the human RNA topoisomerase, and demonstrated the structural elements that kinetically modulate the DNA and RNA topoisomerase activities of TOP3B.
- Xi Yang
- , Sourav Saha
- & Yves Pommier
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Article
| Open AccessA comprehensive thermodynamic model for RNA binding by the Saccharomyces cerevisiae Pumilio protein PUF4
Traditional genomic methods identify RNA-binding proteins (RBPs) and the genes they regulate, but do not provide predictive models. The authors used an emerging technology to obtain a complete thermodynamic model for RNA binding to the PUF4 RBP.
- Christoph Sadée
- , Lauren D. Hagler
- & Daniel Herschlag
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Article
| Open AccessReactivity-dependent profiling of RNA 5-methylcytidine dioxygenases
Kleiner and co-workers profile RNA 5-methylcytidine (m5C) dioxygenase enzymes using an activity-based metabolic probing strategy. They reveal ALKBH1 as the major 5-formylcytidine (f5C) writer and characterize modification sites across mRNA and tRNA.
- A. Emilia Arguello
- , Ang Li
- & Ralph E. Kleiner
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Article
| Open AccessN6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis
Ma et al. profile the dynamic landscape of m6A during pancreatic differentiation, and identify ALKBH5 as an essential m6A regulator supporting pancreatic differentiation, indicating a role for m6A-mediated mRNA metabolism in cell-fate specification.
- Xiaojie Ma
- , Jie Cao
- & Saiyong Zhu
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Article
| Open AccessSingle-molecule FRET uncovers hidden conformations and dynamics of human Argonaute 2
Single-molecule FRET measurements provide detailed insights into the conformational states and dynamics of human Argonaute 2 that are required for its function at the core of the eukaryotic RNA silencing pathway.
- Sarah Willkomm
- , Leonhard Jakob
- & Dina Grohmann
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Article
| Open AccessSimple synthesis of massively parallel RNA microarrays via enzymatic conversion from DNA microarrays
RNA microarrays have many potential applications, but are difficult to produce. Here, the AUs present a method for converting commercial, customizable DNA microarrays into RNA microarrays using an accessible three-step process involving primer photocrosslinking, extension, and template degradation.
- Erika Schaudy
- , Kathrin Hölz
- & Mark M. Somoza
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Article
| Open AccessLimited effects of m6A modification on mRNA partitioning into stress granules
Recent studies proposed that m6A modification in mammalian mRNAs increases their recruitment to stress granule. However, here the authors observed that m6A modification has a limited effect on mRNA entry into stress granules.
- Anthony Khong
- , Tyler Matheny
- & Roy Parker
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Article
| Open AccessEmergent properties as by-products of prebiotic evolution of aminoacylation ribozymes
Complex biochemical systems exhibit traits that appear to be highly adapted. Studies of catalytic RNA demonstrate that adaptive traits, such as increased specificity and error tolerance, could originate as evolutionary by-products.
- Evan Janzen
- , Yuning Shen
- & Irene A. Chen
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Article
| Open AccessProbing TDP-43 condensation using an in silico designed aptamer
Here, the authors generated an artificial RNA molecule, or aptamer, specific for the Amyotrophic Lateral Sclerosis protein TDP-43. By interacting avidly with its target, the aptamer can be exploited to track TDP-43 phase transition in vitro and in cells.
- Elsa Zacco
- , Owen Kantelberg
- & Gian Gaetano Tartaglia
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Article
| Open AccessRNase III CLASH in MRSA uncovers sRNA regulatory networks coupling metabolism to toxin expression
Regulatory small RNA (sRNA) interact with mRNAs to regulate their stability, transcription, and translation via diverse mechanisms. Here, McKellar et al. apply RNase IIICLASH of multi-drug resistant Staphylococcus aureus under different culture conditions to link the network of RNA-RNA interactions to environmental conditions and find that the production of small membrane-permeabilizing toxins is strongly regulated by sRNAs.
- Stuart W. McKellar
- , Ivayla Ivanova
- & Sander Granneman
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Article
| Open AccessHydrophobic-cationic peptides modulate RNA polymerase ribozyme activity by accretion
Macromolecular aggregates may have played an important role in the origin of life. Here, the authors report hydrophobic-cationic peptides that form insoluble aggregates, which reversibly accrete RNA on their surfaces, and enhance RNA polymerization by a ribozyme.
- Peiying Li
- , Philipp Holliger
- & Shunsuke Tagami
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Article
| Open AccessThe RNA-bound proteome of MRSA reveals post-transcriptional roles for helix-turn-helix DNA-binding and Rossmann-fold proteins
RNA-binding proteins play key roles in controlling gene expression in many organisms. Here, Chu et al. identify hundreds of RNA-binding proteins in methicillin-resistant Staphylococcus aureus, and show that a major transcription factor uses its helix-turn-helix domain to bind RNAs near intrinsic transcription terminators.
- Liang-Cui Chu
- , Pedro Arede
- & Sander Granneman
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Article
| Open AccessRNA supply drives physiological granule assembly in neurons
RNA granules are important regulators of RNA metabolism. Here the authors report that RNA granules containing RNA helicase DDX6 disassemble during neuronal maturation.
- Karl E. Bauer
- , Niklas Bargenda
- & Michael A. Kiebler
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Article
| Open AccessHDLBP binds ER-targeted mRNAs by multivalent interactions to promote protein synthesis of transmembrane and secreted proteins
RNA binding protein HDLBP (or Vigilin) localizes in the endoplasmic reticulum (ER) membrane. Here the authors show that HDLBP contributes to translation of ER-targeted mRNAs.
- Ulrike Zinnall
- , Miha Milek
- & Markus Landthaler
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Article
| Open AccessNucleotide-amino acid π-stacking interactions initiate photo cross-linking in RNA-protein complexes
Although UV-induced cross-linking is a widely used method to study RNA-protein complexes, the cross-linking reactions are poorly understood. Here, the authors show that π-stacking interactions between nucleobases and aromatic amino acids play a key role in the cross-linking process.
- Anna Knörlein
- , Chris P. Sarnowski
- & Jonathan Hall
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Article
| Open AccessCharacterization of RNA content in individual phase-separated coacervate microdroplets
Here, the authors demonstrate that single cell RNA sequencing technology can be leveraged to characterize RNA content of individual membrane-free condensates formed by liquid-liquid phase separation processes such as coacervation.
- Damian Wollny
- , Benjamin Vernot
- & Barbara Treutlein
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Article
| Open AccessRegulated IRE1α-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer
IRE1α cleaves several mRNAs upon accumulation of misfolded proteins. Here the authors show that active IRE1α cleaves DGAT2 mRNA encoding the rate-limiting enzyme in the synthesis of triacylglycerols, suggesting a role of IRE1α in reprogramming lipid metabolism in cancer cells.
- Aitor Almanza
- , Katarzyna Mnich
- & Afshin Samali
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Article
| Open AccessEnhancer RNAs stimulate Pol II pause release by harnessing multivalent interactions to NELF
Enhancer RNAs (eRNAs) can stimulate gene transcription through various mechanisms. Here, the authors identify the molecular features within eRNAs that are critical for their action in facilitating RNA Polymerase II release from the paused state.
- Vladyslava Gorbovytska
- , Seung-Kyoon Kim
- & Claus-D. Kuhn
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| Open AccessPytheas: a software package for the automated analysis of RNA sequences and modifications via tandem mass spectrometry
RNA modifications represent a critical aspect of RNA biology that is not well suited to sequencing methods. Here, the authors provide a software tool for automated analysis of RNA tandem mass spectra with full support of modifications, isotope labelling, and control of false discovery rate.
- Luigi D’Ascenzo
- , Anna M. Popova
- & James R. Williamson
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Article
| Open AccessCFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway
Currently, there is no therapy for patients with cystic fibrosis caused by nonsense mutations. Here the authors show that CFTR mRNAs with nonsense codons are predominantly degraded by the SMG6-mediated branch of the NMD pathway, providing potential therapeutic strategies for the devastating disease.
- Edward J. Sanderlin
- , Melissa M. Keenan
- & Lulu Huang
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Article
| Open AccessTRMT6/61A-dependent base methylation of tRNA-derived fragments regulates gene-silencing activity and the unfolded protein response in bladder cancer
RNA modifications are important regulators of RNA biology. Here we report N1-methyladenosine (m1A) enrichment on 22-nucleotide tRNA fragments and its effect on gene-silencing. Higher level of m1A in bladder cancer is accompanied by gene dysregulation in unfolded protein response.
- Zhangli Su
- , Ida Monshaugen
- & Anindya Dutta
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Article
| Open AccessDENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion
Several mechanisms have been associated with transcriptional and post-transcriptional regulation of PD-L1 in cancer. Here the authors show that a RNA binding protein, DENR, positively regulates the translation of JAK2 and induces PD-L1 expression in tumor cells, associated with immune evasion.
- Baiwen Chen
- , Jiajia Hu
- & Hua-Bing Li
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Article
| Open AccessLow complexity RGG-motif sequence is required for Processing body (P-body) disassembly
Processing bodies (PBs) are higher order RNA-protein complexes that determine mRNA fate. Here, the authors show Sbp1 is responsible for PB disassembly and pinpoint a repeats of arginine and glycine (RGG) motif in Sbp1 that play a key role.
- Raju Roy
- , Gitartha Das
- & Purusharth I. Rajyaguru
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Article
| Open AccessReprogrammed tracrRNAs enable repurposing of RNAs as crRNAs and sequence-specific RNA biosensors
In type II CRISPR systems, the guide RNA (gRNA) comprises a CRISPR RNA (crRNA) and a hybridized trans-acting CRISPR RNA (tracrRNA), both being essential in guided DNA targeting functions. Here the authors investigate the programmability of crRNA-tracrRNA hybridization for Cas9 and apply this to biosensing.
- Yang Liu
- , Filipe Pinto
- & Baojun Wang
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Article
| Open AccessSHAPE-guided RNA structure homology search and motif discovery
SHAPEwarp is a method that allows identifying structurally-similar RNAs by direct comparison of reactivity profiles derived from chemical probing experiments. Its application to viral genomes identified conserved RNA structure elements.
- Edoardo Morandi
- , Martijn J. van Hemert
- & Danny Incarnato
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Article
| Open AccessCombinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics
The authors develop an RNA sequencing-based platform, PERSIST-seq, to simultaneously delineate in-cell mRNA stability, ribosome load, and in-solution stability of a diverse mRNA library to derive design principles for improved mRNA therapeutics.
- Kathrin Leppek
- , Gun Woo Byeon
- & Rhiju Das
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Article
| Open AccessSiwi cooperates with Par-1 kinase to resolve the autoinhibitory effect of Papi for Siwi-piRISC biogenesis
Siwi-piRISC protects the germline genome from DNA damage caused by selfish movement of transposons by suppressing their expression. Here, the authors show how molecularly Papi, which plays an important role in the production of Siwi-piRISC, cooperates with Par-1 kinase to ensure the accumulation of Siwi-piRISC in germ cells.
- Hiromi Yamada
- , Kazumichi M. Nishida
- & Mikiko C. Siomi
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Article
| Open AccessRational design of hairpin RNA excited states reveals multi-step transitions
RNA molecules exhibit conformational fluctuations between ground states and excited states. Here the authors designed and verified small hairpin RNAs with predefined secondary structure reshufflings. In light of Van’t Hoff analysis and accelerated molecular dynamics simulation, a mechanism of multistep sequential transition has been revealed.
- Ge Han
- & Yi Xue
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Article
| Open AccessAn RNA-binding protein acts as a major post-transcriptional modulator in Bacillus anthracis
HitRS is a two-component system that responds to cell envelope damage in the bacterium Bacillus anthracis. Here, the authors identify an RNA-binding protein that regulates HitRS function by modulating the stability of the hitRS mRNA. In addition, the protein binds to over 70 RNAs and affects the expression of genes involved in multiple cellular processes.
- Hualiang Pi
- , Andy Weiss
- & Eric P. Skaar
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Article
| Open AccessRNA G-quadruplex in TMPRSS2 reduces SARS-CoV-2 infection
Understanding the mechanisms of SARS-CoV-2 infection is important to control the pandemic. Here the authors show the biological and pathological role of RNA G-quadruplex structure in both SARS-CoV-2 genome and host factors, particularly TMPRSS2.
- Geng Liu
- , Wenya Du
- & Xianghui Fu
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Article
| Open AccessThe methyl phosphate capping enzyme Bmc1/Bin3 is a stable component of the fission yeast telomerase holoenzyme
There exists a remarkable evolutionary breadth of telomerase holoenzyme components among eukaryotes. Here the authors report that the fission yeast methyl phosphate capping enzyme Bin3/Bmc1 regulates telomerase activity by promoting holoenzyme formation.
- Jennifer Porat
- , Moaine El Baidouri
- & Mark A. Bayfield
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Article
| Open AccessCo-translational assembly orchestrates competing biogenesis pathways
The biogenesis of nuclear pores imposes a logistic challenge for cells. Here, the authors investigate structural motifs for co-translational interactions in nucleoporins and find that co-translational assembly events differ between paralogous assembly pathways thus contributing to faithful assembly.
- Maximilian Seidel
- , Anja Becker
- & Martin Beck
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Article
| Open AccessLandscape of adenosine-to-inosine RNA recoding across human tissues
Gabay et al. provide a highly-accurate atlas of recoding by A-to-I RNA editing in human, profiled across tissues and cell subpopulations. Most highly edited sites are evolutionary conserved in non-primate mammals, attesting for adaptation.
- Orshay Gabay
- , Yoav Shoshan
- & Eli Eisenberg
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Article
| Open AccessSecondary structural ensembles of the SARS-CoV-2 RNA genome in infected cells
Lan et al. report RNA structure ensembles across the entire SARSCoV-2 genome in infected human cells at single nucleotide resolution. They find alternative RNA conformations critical for promoting near-native frameshifting rates in ORF1ab.
- Tammy C. T. Lan
- , Matty F. Allan
- & Silvi Rouskin
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Article
| Open AccessCrosstalk between CRISPR-Cas9 and the human transcriptome
The off-target effects of CRISPR-Cas9 are thought to be mediated by its cognate guide RNA. Here the authors show that Cas9 independently interacts with the human transcriptome, correlating with elevated RNA editing even under guide RNA co-expression.
- Aaron A. Smargon
- , Assael A. Madrigal
- & Gene W. Yeo
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Article
| Open AccessSmall Cajal body-associated RNA 2 (scaRNA2) regulates DNA repair pathway choice by inhibiting DNA-PK
Proper repair of DNA double-strand breaks is essential for genomic stability. Here, the authors report that a long non-coding RNA, scaRNA2, inhibits DNA-PK and thereby regulates the choice between error-prone NHEJ and error-free HR DNA repair.
- Sofie Bergstrand
- , Eleanor M. O’Brien
- & Marianne Farnebo
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Article
| Open AccessSpecific length and structure rather than high thermodynamic stability enable regulatory mRNA stem-loops to pause translation
This study shows that rather than high thermodynamic stability, specific length and structure enable regulatory mRNA stem-loops to pause translation. These findings aid identification of new regulatory mRNA stem-loops.
- Chen Bao
- , Mingyi Zhu
- & Dmitri N. Ermolenko
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Article
| Open AccessChemical reversible crosslinking enables measurement of RNA 3D distances and alternative conformations in cells
Determination of RNA 3D structures in vivo is a challenging problem. Here, the authors describe a chemical crosslinking method (SHARC) that they use in combination with RNA sequencing to measure distances between nucleotides in RNA 3D structures.
- Ryan Van Damme
- , Kongpan Li
- & Willem A. Velema
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Article
| Open AccessA late-stage assembly checkpoint of the human mitochondrial ribosome large subunit
Rebelo-Guiomar et al. unveil late stage assembly intermediates of the human mitochondrial ribosome by inactivating the methyltransferase MRM2 in cells. Absence of MRM2 impairs organismal homeostasis, while its catalytic activity is dispensable for mitoribosomal biogenesis.
- Pedro Rebelo-Guiomar
- , Simone Pellegrino
- & Michal Minczuk
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Article
| Open AccessThe RNA methyltransferase METTL8 installs m3C32 in mitochondrial tRNAsThr/Ser(UCN) to optimise tRNA structure and mitochondrial translation
RNA modifications are key regulators of RNA functions. Here, the authors identify METTL8 as the enzyme installing m3C32 in mitochondrial tRNAThr/Ser(UCN). Lack of these modifications affects tRNA structure and impairs mitochondrial translation.
- Nicole Kleiber
- , Nicolas Lemus-Diaz
- & Markus T. Bohnsack
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Article
| Open AccessA small RNA that cooperatively senses two stacked metabolites in one pocket for gene control
Riboswitches contain an aptamer domain that recognizes a metabolite and an expression platform that regulates gene expression. Here the authors report the crystal structure of a preQ1-sensing riboswitch from Carnobacterium antarcticus that shows two metabolites in a single binding pocket.
- Griffin M. Schroeder
- , Chapin E. Cavender
- & Joseph E. Wedekind
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Article
| Open AccessDecoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α
IRE1 helps mitigate endoplasmic-reticulum stress by cleaving specific mRNAs at a conserved sequence endomotif via regulated IRE1-dependent decay (RIDD). Here the authors discover a more promiscuous IRE1 activity dubbed RIDD lacking endomotif (RIDDLE).
- Adrien Le Thomas
- , Elena Ferri
- & Avi Ashkenazi