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| Open AccessNAIL-MS reveals the repair of 2-methylthiocytidine by AlkB in E. coli
Bacterial tRNA is modified by thiolation of nucleosides. Here the authors identify 2-methylthiocytidine in bacterial tRNA using nucleic acid isotope labeling coupled mass spectrometry. Exposure to methylating agents converts 2-thiocytidine to 2-methylthiocytidine, which is repaired by demethylase AlkB in vivo.
- Valentin F. Reichle
- , Dimitar P. Petrov
- & Stefanie Kellner
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Article
| Open AccessBiogenesis and functions of aminocarboxypropyluridine in tRNA
E. coli and human tRNAs contain 3-(3-amino-3-carboxypropyl)uridine (acp3U) modification. Here the authors identify E. coli TapT and human DTWD1/2 as tRNA aminocarboxypropyltransferases responsible for acp3U formation. Inhibition of acp3U modification results in genome instability in heat-stressed E. coli and growth defects in human cells.
- Mayuko Takakura
- , Kensuke Ishiguro
- & Tsutomu Suzuki
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Article
| Open AccessPoly(A) inclusive RNA isoform sequencing (PAIso−seq) reveals wide-spread non-adenosine residues within RNA poly(A) tails
The poly(A) tails on mRNA are vital for their function but it is difficult to map full-length sequences of mRNA isoforms with the entire poly(A) tails. Here the authors develop PAIso−seq which can measure isoform specific poly(A) tail length and base composition at single-cell sensitivity.
- Yusheng Liu
- , Hu Nie
- & Falong Lu
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Article
| Open AccessAntibody cross-reactivity accounts for widespread appearance of m1A in 5’UTRs
N1-methyladenosine (m1A) was recently reported as a new mRNA modification but its prevalence has been controversial. Here the authors showed that m1A, if present in mRNA, is at very low stoichiometry, with the notable exception of MT-ND5. Further, they show that the previously reported enrichment of m1A near the start of transcripts are false-positive identifications due to cross-reactivity of the commonly used m1A antibody with mRNA caps.
- Anya V. Grozhik
- , Anthony O. Olarerin-George
- & Samie R. Jaffrey
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Article
| Open AccessN6-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis
Liver metastasis of colorectal cancer leads to poor prognosis. Here the authors report that an N6-methyladenosine modified circular RNA is upregulated in colorectal cancer and promotes liver metastasis by enhancing the stability of HMGA2 mRNA.
- Ri-Xin Chen
- , Xin Chen
- & Dan Xie
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Article
| Open AccessN6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis
Erythropoiesis can be regulated by transcriptional, epigenetic, and post-transcriptional mechanisms. Here the authors report that N6-methyladenosine mRNA methyltransferase complex stimulates erythropoiesis by promoting translation of specific mRNAs.
- Daniel A. Kuppers
- , Sonali Arora
- & Patrick J. Paddison
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| Open AccessAccurate detection of m6A RNA modifications in native RNA sequences
We currently lack generic methods to map RNA modifications across the entire transcriptome. Here, the authors demonstrate that m6A RNA modifications can be detected with high accuracy using nanopore direct RNA sequencing.
- Huanle Liu
- , Oguzhan Begik
- & Eva Maria Novoa
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Article
| Open AccessDefects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome
The biosynthesis of N6-threonylcarbamoylated adenosine 37 in tRNA (t6A) involves the YRDC enzyme and the KEOPS complex. Here, the authors report mutations in YRDC and the KEOPS component GON7 in Galloway-Mowat syndrome and determine the crystal structure of a GON7-containg subcomplex that suggests a role in KEOPS complex stability.
- Christelle Arrondel
- , Sophia Missoury
- & Géraldine Mollet
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Article
| Open AccessHSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N6-methyladenosine
Cells respond to heat shock with transcriptional and translational adaptations but how HSP90 inhibition alters the heat shock proteome is largely unclear. Here, the authors analyze proteome changes upon HSP90 inhibition and show that an m6A-mediated mechanism contributes to the heat shock-induced upregulation of DNAJB4.
- Weili Miao
- , Lin Li
- & Yinsheng Wang
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Article
| Open AccessModification of messenger RNA by 2′-O-methylation regulates gene expression in vivo
The post-transcriptional modification of mRNAs provides an additional layer to gene expression regulation. Here the authors show that 2′-O-methylation mediated by box C/D snoRNAs and fibrillarin can inhibit the translation of target mRNAs.
- Brittany A. Elliott
- , Hsiang-Ting Ho
- & Christopher L. Holley
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Article
| Open Accessm6A modification of a 3′ UTR site reduces RME1 mRNA levels to promote meiosis
Ime4p is a yeast N6-methyladenosine (m6A) methyltransferase with an unknown role in meiosis. Rme1p is a repressor of meiosis. Here the authors show that Ime4p methylates RME1 3′ UTR to reduce its expression and enable meiosis, thus providing an example of an m6A site with a physiological role.
- G. Guy Bushkin
- , David Pincus
- & Gerald R. Fink
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Article
| Open AccessTime-resolved NMR monitoring of tRNA maturation
Transfer RNA (tRNA) is regulated by RNA modifications. Here the authors employ time-resolved NMR to monitor modifications of yeast tRNAPhe in cellular extracts, revealing a sequential order and cross-talk between modifications.
- Pierre Barraud
- , Alexandre Gato
- & Carine Tisné
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Article
| Open AccessDual pathways of tRNA hydroxylation ensure efficient translation by expanding decoding capability
5-carboxymethoxyuridine (cmo5U) is one of the RNA modifications found in bacterial tRNA anticodons. Here the authors show that the first step of cmo5U biosynthesis from uridine is mediated by either one of two parallel factors, TrhP or TrhO, and that cmo5U modification is required for efficient translation.
- Yusuke Sakai
- , Satoshi Kimura
- & Tsutomu Suzuki
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Article
| Open AccessCrystal structure of the Lin28-interacting module of human terminal uridylyltransferase that regulates let-7 expression
Terminal uridylyltransferase 4/7 (TUT4/7) binds to Lin28 and modifies let-7 precursor (pre-let-7) to regulate cell differentiation and proliferation. Here the authors report the crystal structure of the N-terminal Lin28-interacting module of TUT4, showing a role of the N-terminal zinc finger domain in stabilizing the Lin28:pre-let-7:TUT4 ternary complex.
- Seisuke Yamashita
- , Takashi Nagaike
- & Kozo Tomita
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Article
| Open AccessRNA modification landscape of the human mitochondrial tRNALys regulates protein synthesis
Mutations in mitochondrially-encoded tRNA genes can lead to mitochondrial disorders. Here the authors use next generation RNA sequencing to reveal the role of a N1 -methyladenosine modification in tRNALys MERR patients for translation elongation and the stability of selected nascent chains.
- Uwe Richter
- , Molly E. Evans
- & Brendan J. Battersby
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Article
| Open AccessHuR regulates telomerase activity through TERC methylation
Mutations in the RNA component TERC can cause telomerase dysfunction but the underlying mechanisms are largely unknown. Here, the authors show that RNA-binding protein HuR regulates telomerase function by enhancing the methylation of TERC, which is impaired by several disease-relevant TERC mutations.
- Hao Tang
- , Hu Wang
- & Wengong Wang
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Article
| Open AccessCO2-sensitive tRNA modification associated with human mitochondrial disease
Transfer RNA modifications play critical roles in protein synthesis. Here the authors reveal the t6A37 tRNA modification is dynamically regulated by sensing intracellular CO2 concentration in mitochondria, implying metabolic regulation of protein synthesis.
- Huan Lin
- , Kenjyo Miyauchi
- & Tsutomu Suzuki
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| Open AccessDetecting RNA base methylations in single cells by in situ hybridization
Methylated RNA bases influence many life processes, but current detection methods lack the ability to detect individual methylations in single cells. Here, the authors use fluorescence hybridization probes sensitive to methylation to detect specific epitranscriptomic modifications at the single-cell level.
- Rohan T. Ranasinghe
- , Martin R. Challand
- & David Klenerman
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Article
| Open AccessMolecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1
RNA-binding protein hnRNP A2/B1 is suggested to promote miRNA processing as a m6A 'reader'. Here, the authors determine crystal structures of RRM domains of hnRNP A2/B1 in complex with various RNA substrates and determine that hnRNP A2/B1 may function as an auxiliary factor in 'm6A switch' instead.
- Baixing Wu
- , Shichen Su
- & Jinbiao Ma
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Article
| Open AccessThe m6A pathway facilitates sex determination in Drosophila
N6-methyladenosine (m6A) is a conserved RNA modification that has recently emerged as an important regulator of messenger RNA processing and activity. Here, the authors provide evidence that m6A pathway facilitates female-specific splicing of Sxl, regulating sex determination in Drosophila.
- Lijuan Kan
- , Anya V. Grozhik
- & Eric C. Lai
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Article
| Open AccessYTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex
The YTHDF family of proteins are able to bind and regulate the stability of methylated N6 RNA. Here the authors show that this decreased m6A RNA stability is mediated by direct recruitment of the CCR4–NOT deadenylase complex through YTHDF proteins.
- Hao Du
- , Ya Zhao
- & Ligang Wu
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Article |
Unique features of the m6A methylome in Arabidopsis thaliana
Modification of mRNA with N6-methyladenosine (m6A) is proposed to regulate transcript stability. Here, Jia et al. uncover plant-specific features in the m6A methylome of Arabidopsis, such as methylation enrichment around the start codon, and suggest a positive role in gene expression.
- Guan-Zheng Luo
- , Alice MacQueen
- & Chuan He
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Global 3′ UTR shortening has a limited effect on protein abundance in proliferating T cells
The use of alternative polyadenylation sites can potentially result in mRNA being more or less susceptible to interaction with modulators of translation or stability. Here Gruber et al. find that the shortening of 3′UTRs observed in proliferating T cells does not significantly impact protein abundance.
- Andreas R. Gruber
- , Georges Martin
- & Mihaela Zavolan
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Article |
FTO-mediated formation of N6-hydroxymethyladenosine and N6-formyladenosine in mammalian RNA
Internal modifications in mRNA and non-coding RNA are necessary for modulating various intracellular signalling pathways. In this study, the authors report novel modifications resulting from oxidative RNA demethylation, which regulate RNA–protein interactions affecting gene expression.
- Ye Fu
- , Guifang Jia
- & Chuan He
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Reprogramming of tRNA modifications controls the oxidative stress response by codon-biased translation of proteins
In response to stress, yeast cells selectively translate proteins that can enhance cell survival. In this study, the authors find that tRNALEU(CAA)in yeast cells is modified in response to oxidative stress by a methyltransferase and this results in the selective translation of the mRNA for these genes.
- Clement T.Y. Chan
- , Yan Ling Joy Pang
- & Peter C. Dedon
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Article
| Open AccessSerine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition
Phosphorylation of the carboxy-terminal domain of RNA polymerase II is important for controlling gene transcription. In this study, the transcription elongation factor Tefb is shown to phosphorylate serine-5 and its activity is enhanced when the polymerase is already phosphorylated on serine-7.
- Nadine Czudnochowski
- , Christian A. Bösken
- & Matthias Geyer
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Article |
The tRNA methyltransferase NSun2 stabilizes p16INK4 mRNA by methylating the 3′-untranslated region of p16
The expression of the tumour suppressor p16 is frequently lost in cancer. Zhanget al. show in cultured cells that p16 mRNA levels are stabilised by methylation of the 3′-untranslated region by the tRNA methyltransferase NSun2, revealing a new mechanism for regulating p16.
- Xiaotian Zhang
- , Zhenyun Liu
- & Wengong Wang