Featured
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Letter |
The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution
Transcriptome-wide mapping of N1-methyladenosine (m1A) at single-nucleotide resolution reveals m1A to be scarce in cytoplasmic mRNA, to inhibit translation, and to be highly dynamic at a single site in a mitochondrial mRNA.
- Modi Safra
- , Aldema Sas-Chen
- & Schraga Schwartz
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Letter |
Dynamic landscape and regulation of RNA editing in mammals
Using the GTEx data and others, a comprehensive analysis of adenosine-to-inosine RNA editing in mammals is presented; targets of the various ADAR enzymes are identified, as are several potential regulators of editing, such as AIMP2.
- Meng How Tan
- , Qin Li
- & Jin Billy Li
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Letter |
mRNA 3′ uridylation and poly(A) tail length sculpt the mammalian maternal transcriptome
TUT4 and TUT7 mediate 3′ uridylation of mRNA transcripts, preferentially those with short poly(A) tails; in the absence of TUT4 and TUT7, oocytes cannot mature and female mice are infertile.
- Marcos Morgan
- , Christian Much
- & Dónal O’Carroll
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Letter |
m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways
The authors assess the role of N6-methyladenosine in T cell development and function, and show that RNA methylation controls T cell homeostasis by regulating IL-7-mediated STAT5 activation.
- Hua-Bing Li
- , Jiyu Tong
- & Richard A. Flavell
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Article |
RNA phase transitions in repeat expansion disorders
Nucleotide repeat expansions create templates for multivalent base-pairing, which causes RNA to undergo a sol–gel phase transition and may explain the formation of nuclear RNA foci that are commonly observed in several neurological and neuromuscular diseases.
- Ankur Jain
- & Ronald D. Vale
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Letter |
Structure of the Cpf1 endonuclease R-loop complex after target DNA cleavage
The structure of Cpf1, a CRISPR–Cas/RNA-guided nuclease, is presented with a three-stranded RNA–DNA loop after cleavage, providing insight into its working mechanism.
- Stefano Stella
- , Pablo Alcón
- & Guillermo Montoya
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Article |
Ensemble cryo-EM elucidates the mechanism of translation fidelity
Structural ensembles of the 70S ribosome bound to cognate or near-cognate charged tRNAs in complex with EF-Tu illustrate the crucial role of the nucleotide G530 in decoding of mRNA, and demonstrate that translational fidelity results from direct control of GTPase by the decoding centre.
- Anna B. Loveland
- , Gabriel Demo
- & Andrei A. Korostelev
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Article |
Structure of a pre-catalytic spliceosome
The cryo-electron microscopy structure of the yeast spliceosome in a pre-catalytic state provides insights into the molecular events leading to formation of the spliceosome active site.
- Clemens Plaschka
- , Pei-Chun Lin
- & Kiyoshi Nagai
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Letter |
Structural basis of CRISPR–SpyCas9 inhibition by an anti-CRISPR protein
The structure of the anti-CRISPR protein AcrIIA4, in complex with a single-guide RNA and Cas9, reveals that the protein inhibits DNA binding and blocks the Cas9 endonuclease active site.
- De Dong
- , Minghui Guo
- & Zhiwei Huang
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Letter |
DND1 maintains germline stem cells via recruitment of the CCR4–NOT complex to target mRNAs
The vertebrate-conserved and germline-specific RNA-binding protein DND1 recruits the CCR4–NOT deadenylase complex to destabilize its mRNA targets and is required for the maintenance of germline stem cells.
- Masashi Yamaji
- , Miki Jishage
- & Thomas Tuschl
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Letter |
RNA m6A methylation regulates the ultraviolet-induced DNA damage response
Methylation at the 6 position of adenosine (m6A) in RNA is rapidly and transiently induced at DNA damage sites in response to ultraviolet irradiation.
- Yang Xiang
- , Benoit Laurent
- & Yang Shi
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Letter |
Editing and methylation at a single site by functionally interdependent activities
The C-to-U deamination at position 32 of tRNAThr in Trypanosoma brucei requires two enzymatic activities and proceeds via formation of a 3-methylcytosine intermediate, supporting the notion of a coupled modification system.
- Mary Anne T. Rubio
- , Kirk W. Gaston
- & Juan D. Alfonzo
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Article |
An Argonaute phosphorylation cycle promotes microRNA-mediated silencing
The application of genome-wide CRISPR–Cas9 screening coupled with a fluorescent reporter to interrogate the microRNA pathway reveals that continual transient phosphorylation of Argonaute 2 is required to maintain the global efficiency of microRNA-mediated repression.
- Ryan J. Golden
- , Beibei Chen
- & Joshua T. Mendell
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Letter |
Structure of a spliceosome remodelled for exon ligation
The cryo-electron microscopy structure of a yeast spliceosome stalled before mature RNA formation provides insight into the mechanism of exon ligation.
- Sebastian M. Fica
- , Chris Oubridge
- & Kiyoshi Nagai
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Article |
Cryo-EM structure of a human spliceosome activated for step 2 of splicing
The cryo-EM structure of the splicing intermediate known as the C* complex from human.
- Karl Bertram
- , Dmitry E. Agafonov
- & Reinhard Lührmann
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Article |
Reversible methylation of m6Am in the 5′ cap controls mRNA stability
Fat mass and obesity-associated protein (FTO) preferentially demethylates m6Am, a modified adenosine that, when present at the 5′ end of certain mRNAs, positively influences mRNA stability by preventing DCP2-mediated decapping.
- Jan Mauer
- , Xiaobing Luo
- & Samie R. Jaffrey
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Letter |
Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans
Precursor mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans and defects in global pre-mRNA splicing associated with age are reduced by dietary restriction via splicing factor 1.
- Caroline Heintz
- , Thomas K. Doktor
- & William B. Mair
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Letter |
m6A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination
Two complementary studies describe how the pervasive N6-methyladenosine modification in mRNA can affect Drosophila sex determination, neuronal function and behaviour.
- Irmgard U. Haussmann
- , Zsuzsanna Bodi
- & Matthias Soller
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Article |
m6A modulates neuronal functions and sex determination in Drosophila
One of the most abundant modifications found in messenger RNAs is N6-methyladenosine (m6A); here, this modification is shown to alter gene expression during sex determination and affect neuronal functions and behaviour in Drosophila via the m6A reader protein YT521-B.
- Tina Lence
- , Junaid Akhtar
- & Jean-Yves Roignant
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Letter |
Structures of riboswitch RNA reaction states by mix-and-inject XFEL serial crystallography
Femtosecond XFEL crystallography is used to identify dynamic changes in the adenine riboswitch aptamer domain, with at least four states identified in real time, two in the apo form before binding and two with the ligand bound.
- J. R. Stagno
- , Y. Liu
- & Y.-X. Wang
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Letter |
Mechanism for DNA transposons to generate introns on genomic scales
The observations that introns are acquired in bursts and that exons are often nucleosome-sized can be explained by the generation of introns from DNA transposons, which insert between nucleosomes.
- Jason T. Huff
- , Daniel Zilberman
- & Scott W. Roy
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Letter |
Two distinct RNase activities of CRISPR-C2c2 enable guide-RNA processing and RNA detection
The CRISPR-associated bacterial enzyme C2c2 is shown to contain two separable, distinct sites for the highly sensitive detection and cleavage of single-stranded RNA.
- Alexandra East-Seletsky
- , Mitchell R. O’Connell
- & Jennifer A. Doudna
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Article |
m6A RNA methylation promotes XIST-mediated transcriptional repression
The methylation of adenosine residues on the long non-coding RNA XIST is essential for X-chromosome transcriptional repression during female mammalian development.
- Deepak P. Patil
- , Chun-Kan Chen
- & Samie R. Jaffrey
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Article |
Cryo-EM structure of the spliceosome immediately after branching
Cryo-EM reveals the configuration of substrate pre-mRNA within the active spliceosome and suggests how remodelling occurs prior to exon ligation.
- Wojciech P. Galej
- , Max E. Wilkinson
- & Kiyoshi Nagai
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Letter |
The mechanism of RNA 5′ capping with NAD+, NADH and desphospho-CoA
RNA caps other than the 7-methylguanylate modification are generated by a distinct mechanism in which caps are added during, not after, transcription initiation through the use of non-canonical initiating nucleotides by RNA polymerases, a finding which has functional consequences.
- Jeremy G. Bird
- , Yu Zhang
- & Bryce E. Nickels
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Article |
Failure of RQC machinery causes protein aggregation and proteotoxic stress
Defects in the ribosome quality control (RQC) complex, which clears proteins that stalled during translation, can cause neurodegeneration; here it is shown that in RQC-defective cells a peptide tail added by the RQC subunit 2 to stalled polypeptides promotes their aggregation and the sequestration of chaperones in these aggregates, affecting normal protein quality control processes.
- Young-Jun Choe
- , Sae-Hun Park
- & F. Ulrich Hartl
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Article |
The dynamic N1-methyladenosine methylome in eukaryotic messenger RNA
Here the m1A modification is discovered in messenger RNA and mapped at the transcriptome-wide level; the modification is conserved, dynamic, accumulates in structured regions around translation initiation sites upstream of the first splice site, and correlates with higher protein expression.
- Dan Dominissini
- , Sigrid Nachtergaele
- & Chuan He
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Article |
Cryo-EM structure of the yeast U4/U6.U5 tri-snRNP at 3.7 Å resolution
A 3.7 Å resolution structure for the yeast U4/U6.U5 tri-snRNP, a complex involved in splicing, allows a better appreciation of the architecture of the tri-snRNP, and offers new functional insights into the activation of the spliceosome and the assembly of the catalytic core.
- Thi Hoang Duong Nguyen
- , Wojciech P. Galej
- & Kiyoshi Nagai
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Article |
The core spliceosome as target and effector of non-canonical ATM signalling
Transcription-blocking DNA lesions result in chromatin displacement of core spliceosomes containing U2 and U5 snRNPs; consequently, R-loops containing the nascent transcript are formed, which activate ATM in a feed-forward fashion to influence spliceosome dynamics and alternative splicing.
- Maria Tresini
- , Daniël O. Warmerdam
- & Jurgen A. Marteijn
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Article |
The architecture of the spliceosomal U4/U6.U5 tri-snRNP
This study determines the structure of the spliceosomal tri-snRNP complex (containing three small nuclear RNAs and more than 30 proteins) by single-particle cryo-electron microscopy; the resolution is sufficient to discern the organization of RNA and protein components involved in spliceosome activation, exon alignment and catalysis.
- Thi Hoang Duong Nguyen
- , Wojciech P. Galej
- & Kiyoshi Nagai
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Letter |
Recursive splicing in long vertebrate genes
Highly conserved recursive splice sites are identified in vertebrates, particularly within long genes encoding proteins that are involved in neuronal development; analysis of the splicing mechanism reveals that such recursive splicing sites can be used to dictate different mRNA isoforms.
- Christopher R. Sibley
- , Warren Emmett
- & Jernej Ule
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Letter |
Genome-wide identification of zero nucleotide recursive splicing in Drosophila
In flies, some introns contain internal splice sites that cause ‘recursive splicing’, a multi-step removal of a single intron; this study demonstrates that the scope of this regulatory mechanism is much more extensive in flies than had been appreciated, and provides details about the recursive splicing process.
- Michael O. Duff
- , Sara Olson
- & Brenton R. Graveley
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Letter |
MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis
The critical effectors of MYC overexpression during lymphomagenesis in transgenic mice are defined.
- Cheryl M. Koh
- , Marco Bezzi
- & Ernesto Guccione
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Letter |
N6-methyladenosine marks primary microRNAs for processing
The addition of the N6-methyladenosine (m6A) mark to primary microRNAs by METTL3 in mammalian cells is found to promote the recognition of these microRNA precursors by DGCR8, a component of the microprocessor complex.
- Claudio R. Alarcón
- , Hyeseung Lee
- & Sohail F. Tavazoie
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Letter |
hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1
A method, termed hiCLIP, has been developed to determine the RNA duplexes bound by RNA-binding proteins, revealing an unforeseen prevalence of long-range duplexes in 3′ untranslated regions (UTRs), and a decreased incidence of SNPs in duplex-forming regions; the results also show that RNA structure is able to regulate gene expression.
- Yoichiro Sugimoto
- , Alessandra Vigilante
- & Jernej Ule
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Letter |
N6-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions
The binding motifs for many RNA-binding proteins are normally buried within structured regions; now, the N6-methyladenosine modification is shown to act as a switch to remodel these regions, expose the motif, and thereby facilitate binding of RNA-binding proteins.
- Nian Liu
- , Qing Dai
- & Tao Pan
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Letter |
NAD captureSeq indicates NAD as a bacterial cap for a subset of regulatory RNAs
A newly developed method, NAD captureSeq, has been used to show that bacteria cap the 5′-ends of some RNAs to protect against degradation, much as happens with eukaryotic messenger RNAs, although with a different modification: nicotinamide adenine dinucleotide.
- Hana Cahová
- , Marie-Luise Winz
- & Andres Jäschke
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Letter |
RNA helicase DDX21 coordinates transcription and ribosomal RNA processing
DEAD-box RNA helicase DDX21 is involved in both the transcription and RNA processing of ribosomal genes in human cells, sensing the transcriptional status of both RNA polymerase I and RNA polymerase II and associating with non-coding RNAs involved in ribonucleoprotein formation, possibly allowing for coordinated regulation of protein synthesis.
- Eliezer Calo
- , Ryan A. Flynn
- & Joanna Wysocka
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Letter |
R-loops induce repressive chromatin marks over mammalian gene terminators
R-loops, which have been considered to be rare and potentially harmful transcriptional by-products, are now shown to be needed for antisense transcription and to induce repressive chromatin marks that reinforce pausing of transcription and thereby enhance its termination.
- Konstantina Skourti-Stathaki
- , Kinga Kamieniarz-Gdula
- & Nicholas J. Proudfoot
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Letter |
Programmable RNA recognition and cleavage by CRISPR/Cas9
In the presence of a short DNA oligonucleotide containing a protospacer adjacent motif, a guide-RNA-programmed Cas9 is able to specifically bind and/or cleave single-stranded RNA—this system can be used to isolate specific endogenous RNA transcripts from a cell lysate without any tag or modification.
- Mitchell R. O’Connell
- , Benjamin L. Oakes
- & Jennifer A. Doudna
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Article |
Crystal structure of a eukaryotic group II intron lariat
This study determines the structure of a branched lariat RNA, providing insights into rearrangement of the intron between the two steps of RNA splicing.
- Aaron R. Robart
- , Russell T. Chan
- & Navtej Toor
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Letter |
Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells
The modification of uridine to pseudouridine is widespread in transfer and ribosomal RNAs but not observed so far in a coding RNA; here a new technique is used to detect this modification on a genome-wide scale, leading to the identification of pseudouridylation in messenger RNAs as well as almost 100 new sites in non-coding RNAs.
- Thomas M. Carlile
- , Maria F. Rojas-Duran
- & Wendy V. Gilbert
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Letter |
Promoter sequences direct cytoplasmic localization and translation of mRNAs during starvation in yeast
Transcription and translation are generally thought of as disconnected processes in eukaryotes; however, under starvation conditions in yeast, the promoter sequence influences not only messenger RNA levels but also several processes downstream of transcription, including the localization of mRNA within the cytoplasm and the translation rate of mRNA.
- Brian M. Zid
- & Erin K. O’Shea
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Letter |
Mechanism of Dis3l2 substrate recognition in the Lin28–let-7 pathway
The structure of mouse Dis3l2 bound to an oligoU substrate shows a funnel-like substrate-binding site with the RNA being fed into the active site along a path that is distinct from that seen in the related catalytic subunit of the exosome — 12 uracils of the oligoU-tailed RNA are recognized in a complex network of interactions, suggesting the basis for target specificity.
- Christopher R. Faehnle
- , Jack Walleshauser
- & Leemor Joshua-Tor
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Letter |
Analysis of orthologous groups reveals archease and DDX1 as tRNA splicing factors
Using a phylogenetic approach, the protein archease is identified as being a subunit of the human transfer RNA splicing ligase, and found to be necessary for full ligase activity, in cooperation with DDX1.
- Johannes Popow
- , Jennifer Jurkin
- & Javier Martinez
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Letter |
CFIm25 links alternative polyadenylation to glioblastoma tumour suppression
CFIm25 is identified as a factor that prevents messenger RNAs being shortened due to altered 3′ polyadenylation, which typically occurs when cells undergo high proliferation and correlates with increased tumorigenic activity in glioblastoma tumours.
- Chioniso P. Masamha
- , Zheng Xia
- & Eric J. Wagner
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Article |
Protein-guided RNA dynamics during early ribosome assembly
Three-colour fluorescence resonance energy transfer and molecular dynamics simulations are used to study the events occurring early in assembly of the 30S ribosome; within a non-native intermediate S4 ribosomal protein–16S RNA structure, S4 is capable of altering the RNA helix dynamics to facilitate conformation changes that enable subsequent protein binding.
- Hajin Kim
- , Sanjaya C. Abeysirigunawarden
- & Sarah A. Woodson
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Letter |
Landscape and variation of RNA secondary structure across the human transcriptome
An RNA secondary structure (RSS) map of coding and noncoding RNA from a human family (two parents and their child) is produced; this reveals that approximately 15% of all transcribed single nucleotide variants (SNVs) alter local RNA structure, and these SNVs are depleted in certain locations, suggesting that particular RNA structures are important at those sites.
- Yue Wan
- , Kun Qu
- & Howard Y. Chang
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Letter |
N6-methyladenosine-dependent regulation of messenger RNA stability
The mRNAs of higher eukaryotes are extensively modified internally with N6-methyladenosine, but the specific functional role of this modification has been unclear; here this modification on mRNA is shown to be recognized by several proteins, the modification and its recognition serve to regulate the RNA’s lifetime.
- Xiao Wang
- , Zhike Lu
- & Chuan He