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| Open AccessIn vivo PAR-CLIP (viP-CLIP) of liver TIAL1 unveils targets regulating cholesterol synthesis and secretion
Here the authors develop viP-CLIP, a technique allowing the identification of RNA binding proteins (RBP) targets in mouse tissues, and identify the RBP Tial1 as a regulator of cholesterol metabolism in the liver.
- Hasan Vatandaslar
- , Aitor Garzia
- & Markus Stoffel
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Article
| Open AccessThe preference signature of the SARS-CoV-2 Nucleocapsid NTD for its 5’-genomic RNA elements
SARS-CoV-2 genome turnover is mediated by its N protein, but precise parameters driving the necessary RNA specificity have remained enigmatic. Here, Korn et al. reveal N’s N-terminal domain to distinguish regulatory viral RNA motifs with a preference for transiently folded elements of functional impact.
- Sophie Marianne Korn
- , Karthikeyan Dhamotharan
- & Andreas Schlundt
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| Open AccessIntracellular RNA and DNA tracking by uridine-rich internal loop tagging with fluorogenic bPNA
Commonly used protein-based tools to monitor intracellular RNA and DNA can impact steric accessibility and native nucleic acid biology. Here, the authors show that fluorogenic uridine-rich internal loop tagging bPNA probes can be used to label nucleic acids in fixed and live cells.
- Yufeng Liang
- , Sydney Willey
- & Dennis Bong
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Article
| Open AccessCo-crystal structures of the fluorogenic aptamer Beetroot show that close homology may not predict similar RNA architecture
The recently discovered aptamer Beetroot is a homodimeric RNA that binds and activates DFAME, a conditional, red-shifted fluorophore derived from GFP. Here the authors determine the Beetroot-DFAME co-crystal structure, which is distinctively different from that of similar RNA aptamer Corn.
- Luiz F. M. Passalacqua
- , Mary R. Starich
- & Adrian R. Ferré-D’Amaré
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| Open AccessCap analogs with a hydrophobic photocleavable tag enable facile purification of fully capped mRNA with various cap structures
Removing immunogenic uncapped mRNA from transcribed mRNA can be challenging, but is critical in mRNA research and clinical applications such as vaccines. Here, authors develop hydrophobic photocaged tag-modified cap analogs, which can be used to separate capped mRNA from uncapped mRNA, with subsequent tag removal using photo-irradiation.
- Masahito Inagaki
- , Naoko Abe
- & Hiroshi Abe
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| Open AccessObservation of structural switch in nascent SAM-VI riboswitch during transcription at single-nucleotide and single-molecule resolution
Observation of single nascent RNA at single-nucleotide resolution enables building a conformation landscape of how RNAs change during transcription. Here the authors develop a method to monitor the conformational change of individual SAM-VI riboswitch RNA (riboSAM) during transcription at single-nucleotide resolution as it is synthesized by transcription.
- Yanyan Xue
- , Jun Li
- & Yu Liu
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Article
| Open AccessRNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells
Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here they show that SYNCRIP safeguards HSC self-renewal during regenerative stress by maintaining both proteostasis and CDC42-regulated cell polarity.
- Florisela Herrejon Chavez
- , Hanzhi Luo
- & Michael G. Kharas
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Article
| Open AccessCopy number variation in tRNA isodecoder genes impairs mammalian development and balanced translation
Enigmatically tRNA genes exist in several hundred copies in mammalian genomes. Here the authors find a precipitous failure of development and increased amino acid misincorporation upon systematic elimination of tRNA-Phe genes in mice using CRISPR.
- Laetitia A. Hughes
- , Danielle L. Rudler
- & Aleksandra Filipovska
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Article
| Open AccessScreening of Drosophila microRNA-degradation sequences reveals Argonaute1 mRNA’s role in regulating miR-999
miRNAs typically bind to target mRNAs to induce their degradation but when base-pairing between miRNAs and the target RNAs are extended, miRNAs themselves can be degraded. Here, by employing AGO1-CLASH in Drosophila cells, the authors show that RNA sequence in AGO1 mRNA 3′UTR induces decay of miR-999.
- Peike Sheng
- , Lu Li
- & Mingyi Xie
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Article
| Open AccessCrystal structure of a highly conserved enteroviral 5′ cloverleaf RNA replication element
A cloverleaf-like RNA domain within the enterovirus genome is essential for replication. Here, the authors determine the 1.9 Å resolution crystal structure of such RNA from coxsackievirus B3 – a model enterovirus to study many other human viruses.
- Naba K. Das
- , Nele M. Hollmann
- & Deepak Koirala
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| Open AccessBombyx Vasa sequesters transposon mRNAs in nuage via phase separation requiring RNA binding and self-association
Bombyx Vasa assembles Vasa bodies, the site of transposon silencing by Siwi and Ago3-piRISC formation. Here, the authors show Vasa sequesters transposon mRNAs in Vasa bodies via phase separation requiring RNA binding and self-association of Vasa.
- Hiroya Yamazaki
- , Yurika Namba
- & Mikiko C. Siomi
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Article
| Open AccessMulti-modal quantification of pathway activity with MAYA
Pathways can be activated through various signaling cascades depending on cell type. Here, the authors introduce MAYA, a computational method that can detect and score multiple modes of activation for each pathway, improving the granularity of pathway analysis for single-cell datasets.
- Yuna Landais
- & Céline Vallot
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| Open AccessSnapshots of the second-step self-splicing of Tetrahymena ribozyme revealed by cryo-EM
The Tetrahymena ribozyme changes conformations to perform its self-splicing function. Here, the authors capture six structural snapshots of ribozyme during the second step of self-splicing from a single specimen, revealing the structural basis of how it promotes and coordinates self-splicing reactions.
- Shanshan Li
- , Michael Z. Palo
- & Kaiming Zhang
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| Open AccessWell-TEMP-seq as a microwell-based strategy for massively parallel profiling of single-cell temporal RNA dynamics
Gene expression of cells is a heterogeneous and dynamic program involved in various biological processes. Here, authors develop Well-TEMPseq, a high-throughput, cost-effective, and accurate method for massively parallel profiling of the temporal dynamics of single-cell gene expression.
- Shichao Lin
- , Kun Yin
- & Chaoyong Yang
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| Open AccessPeriodic temperature changes drive the proliferation of self-replicating RNAs in vesicle populations
How primordial cells could achieve inheritance of encapsulated components is still an open question. Here, the authors show that ribozymes can assemble in active forms and replicate in populations of membrane vesicles thanks to freeze-thaw cycles.
- Elia Salibi
- , Benedikt Peter
- & Hannes Mutschler
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| Open AccessEvaluating native-like structures of RNA-protein complexes through the deep learning method
RNA-protein docking is a very challenging area. Here, the authors develop a deep-learning based method, DRPScore, to evaluate RNA-protein complexes. DRPScore is robust and consistently performs better than existing methods on representative testing sets.
- Chengwei Zeng
- , Yiren Jian
- & Yunjie Zhao
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| Open AccessMechanisms of the RNA helicases DDX42 and DDX46 in human U2 snRNP assembly
The U2 snRNP recognizes the intron during spliceosome assembly. Here the authors report the high-resolution structures of two assembly precursors of human U2 snRNP and reveal that the RNA helicases DDX42 and DDX46 are mutually exclusive in terms of SF3B1-binding.
- Fenghua Yang
- , Tong Bian
- & Yigong Shi
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Article
| Open AccessCryo-EM captures early ribosome assembly in action
The production of ribosomes is a precisely orchestrated energy consuming cellular process of highest priority. Here, the authors use cryo-EM to show that bacterial ribosomal subunits, self-assembled from their purified RNA and protein components, mature along parallel pathways.
- Bo Qin
- , Simon M. Lauer
- & Rainer Nikolay
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| Open AccessVisualizing orthogonal RNAs simultaneously in live mammalian cells by fluorescence lifetime imaging microscopy (FLIM)
No multi-color RNA fluorescent tags are currently available for use in live cells. Here, the authors show that fluorescence lifetime imaging microscopy is advantageous for multiplexed RNA visualization while achieving robust cellular contrast.
- Nadia Sarfraz
- , Emilia Moscoso
- & Esther Braselmann
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| Open AccessChemoproteomic discovery of a human RNA ligase
RNA ligases are present across all forms of life. Here, the hitherto uncharacterised human protein C12orf29 was identified as a human enzyme promoting RNA ligation between 5′-PO4 and 3′-OH termini. This data provides the groundwork for establishing a human RNA repair pathway.
- Yizhi Yuan
- , Florian M. Stumpf
- & Andreas Marx
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| Open AccessVisualizing RNA conformational and architectural heterogeneity in solution
RNA conformational heterogeneity is important to diverse functions. Here, the authors use AFM to directly visualize individual RNA molecules that are in various conformational states under near physiological solution conditions for the first time.
- Jienyu Ding
- , Yun-Tzai Lee
- & Yun-Xing Wang
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| Open AccessTwo distinct binding modes provide the RNA-binding protein RbFox with extraordinary sequence specificity
Here the authors show that the RRM of RbFox accomplishes extraordinary sequence specificity by employing functionally and structurally distinct binding modes - one for its cognate RNA and one for all non-cognate RNAs.
- Xuan Ye
- , Wen Yang
- & Fan Yang
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| Open AccessReanalysis of ribosome profiling datasets reveals a function of rocaglamide A in perturbing the dynamics of translation elongation via eIF4A
The compound Rocaglamide A (RocA) is known for repressing translation initiation. Here the authors identify a dual mode of action for RocA in blocking translation initiation and elongation via eIF4A using previous datasets and new analyses.
- Fajin Li
- , Jianhuo Fang
- & Xuerui Yang
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| Open AccessA paralog of Pcc1 is the fifth core subunit of the KEOPS tRNA-modifying complex in Archaea
Many eukaryotic and archaeal tRNAs carry a modified adenosine (t6A) that is synthesized by the KEOPS complex, which is composed of four subunits. A fifth subunit (Gon7) is found only in fungi and metazoa. Here the authors show that archaea also possess a fifth subunit, which is structurally and functionally similar to eukaryotic Gon7.
- Marie-Claire Daugeron
- , Sophia Missoury
- & Tamara Basta
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| Open AccessPreclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation
The search for antivirals against SARS-CoV-2 continue due to the emergence of variants of concerns, able to escape the vaccinal humoral response. In this work, authors pre-clinically explore the potential of kinetin against SARS-CoV-2, which could be used alone or in combination with other antivirals.
- Thiago Moreno L. Souza
- , Vagner D. Pinho
- & Jaime A. Rabi
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Article
| Open AccessDecoding of the ubiquitin code for clearance of colliding ribosomes by the RQT complex
The colliding ribosomes are ubiquitinated by the sensor protein Hel2, leading to noncanonical subunit dissociation by the ribosome associated quality control trigger (RQT) complex. Here the authors reveal the decoding mechanism of the ribosome ubiquitin code by the RQT complex.
- Yoshitaka Matsuo
- , Takayuki Uchihashi
- & Toshifumi Inada
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| Open AccessTargeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation
Here the authors generate an RNA-based platform to neutralize the major epigenetic player DNMT1. Using this targeted approach, aberrant DNA methylation in cancer can be corrected.
- Carla L. Esposito
- , Ida Autiero
- & Annalisa Di Ruscio
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| Open AccessTranslation factor eIF5a is essential for IFNγ production and cell cycle regulation in primary CD8+ T lymphocytes
The translational elongation factor eIF5a may have a function in T cell protein translation. Here the authors show that hypusination of eIF5a or deletion of eIF5a alters the profile of mRNA translation in T cells and that eIF5 regulates the proliferation and effector function of these T cells.
- Thomas C. J. Tan
- , Van Kelly
- & Rose Zamoyska
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| Open AccessBroad misappropriation of developmental splicing profile by cancer in multiple organs
The molecular mechanisms underlying the overlap between oncogenic and embryonic development remain to be explored. Here, the authors use temporal transcriptomic data during development in multiple human organs and suggest the involvement of alternative splicing events, splicing factors, and transcription factors.
- Arashdeep Singh
- , Arati Rajeevan
- & Sridhar Hannenhalli
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| Open AccessDAP5 enables main ORF translation on mRNAs with structured and uORF-containing 5′ leaders
RNA structure and upstream ORFs can modulate the translation of human transcripts. Here, the authors show that structured mRNAs with pervasive uORF translation require DAP5, an eIF4G-like protein, for translation of the main ORF.
- Ramona Weber
- , Leon Kleemann
- & Cátia Igreja
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| Open AccessAltered tRNA processing is linked to a distinct and unusual La protein in Tetrahymena thermophila
La proteins are conserved factors critical for the maturation of RNA polymerase III transcripts. In the ciliate T. thermophila and related alveolates, La proteins have a novel domain arrangement and are linked to a distinct pre-tRNA processing pathway.
- Kyra Kerkhofs
- , Jyoti Garg
- & Mark A. Bayfield
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Article
| Open AccessStructural basis for recognition of transcriptional terminator structures by ProQ/FinO domain RNA chaperones
In this work, the authors determine the crystal structure of a ProQ/FinO RNA chaperone bound to its RNA target. This provides insight into how this family of bacterial proteins recognize transcriptional terminator structures.
- Hyeong Jin Kim
- , Mazzen Black
- & J. N. Mark Glover
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Article
| Open AccessStructure of the IscB–ωRNA ribonucleoprotein complex, the likely ancestor of CRISPR-Cas9
The cryo-EM structure of the IscB–ωRNA–target DNA complex provide insights into the ωRNA-guided DNA cleavage mechanism by IscB and the evolution of the type II CRISPR-Cas9 effector complexes
- Kazuki Kato
- , Sae Okazaki
- & Hiroshi Nishimasu
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| Open AccessRNA-binding proteins of KHDRBS and IGF2BP families control the oncogenic activity of MLL-AF4
The establishment of a mouse model of MLL-AF4-induced leukaemia is a challenge as the introduction of fusion gene of human MLL-AF4 does not cause leukaemia in mice. Here the authors reveal that MLL-AF4 is post-transcriptionally regulated by RNA-binding proteins that inhibits MLL-AF4 translation, thus, hampering MLL-AF4-mediated leukemic transformation.
- Hiroshi Okuda
- , Ryo Miyamoto
- & Akihiko Yokoyama
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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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| 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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| 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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| 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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| 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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| 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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| 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