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| Open AccessThe therapeutic significance of mutational signatures from DNA repair deficiency in cancer
Targeting DNA repair-deficient tumors is one of the most promising therapeutic strategies in cancer research; however, accurately predicting which tumors will respond can be a challenge. Here the authors present a review of the current state of knowledge in DNA repair deficiency across human cancers.
- Jennifer Ma
- , Jeremy Setton
- & Simon N. Powell
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Article
| Open AccessDecoding a cancer-relevant splicing decision in the RON proto-oncogene using high-throughput mutagenesis
Alternative splicing is a critical step in eukaryotic gene expression but its molecular rules are not fully understood. Here, the authors develop a high-throughput mutagenesis approach to comprehensively characterise determinants of alternative splicing for the RON proto-oncogene.
- Simon Braun
- , Mihaela Enculescu
- & Kathi Zarnack
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Article
| Open AccessThe Arp8 and Arp4 module acts as a DNA sensor controlling INO80 chromatin remodeling
INO80 chromatin remodeler plays important roles in transcription, DNA repair, recombination, and heterochromatin maintenance. Here the authors characterise the functional interplay between the actin-related proteins (Arps) in INO80, showing that Arp8 and Arp4 module sense the DNA length separating nucleosomes and regulate nucleosome remodeling.
- Sandipan Brahma
- , Mzwanele Ngubo
- & Blaine Bartholomew
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Article
| Open AccessSUMOylation of VEGFR2 regulates its intracellular trafficking and pathological angiogenesis
VEGFR2 is a central regulator of angiogenesis. Here Zhou et al. report that SUMOylation of VEGFR2 regulates its subcellular localisation and activity, and that endothelial-specific knockout of the SUMO endopeptidase SENP1 protects against VEGFR2-mediated pathological angiogenesis.
- Huanjiao Jenny Zhou
- , Zhe Xu
- & Wang Min
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Article
| Open AccessBiased genome editing using the local accumulation of DSB repair molecules system
Genome editing using CRISPR can be enhanced by manipulating DNA double-strand break repair pathways. Here the authors demonstrate LoAD, local accumulation of repair molecules, which shifts repair to microhomology-mediated end-joining.
- Shota Nakade
- , Keiji Mochida
- & Takashi Yamamoto
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Article
| Open AccessDecoding topologically associating domains with ultra-low resolution Hi-C data by graph structural entropy
Accurate detection of TADs requires ultra-deep sequencing and sophisticated normalisation procedures, which limits the analysis of Hi-C data. Here the authors develop a normalisation-free method to decode the domains of chromosomes (deDoc) that utilizes structural entropy to predict TADs with ultra-low sequencing data.
- Angsheng Li
- , Xianchen Yin
- & Zhihua Zhang
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Article
| Open AccessRevealing circadian mechanisms of integration and resilience by visualizing clock proteins working in real time
The circadian clock proteins KaiA, KaiB, and KaiC reconstitute a circa-24 h oscillation of KaiC phosphorylation in vitro. Here the authors use high-speed atomic force microscopy to visualize in real time and quantify the dynamic interactions of KaiA with KaiC on the sub-second timescale to discover mechanisms of oscillatory resilience.
- Tetsuya Mori
- , Shogo Sugiyama
- & Toshio Ando
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Article
| Open AccessPARP2 mediates branched poly ADP-ribosylation in response to DNA damage
PARP1 and PARP2 of the PARP family enzymes are involved in DNA damage response. Here the authors report PARP2 activation mechanisms and its role in the formation of branched poly(ADP-ribose) chains in response to DNA damage.
- Qian Chen
- , Muzaffer Ahmad Kassab
- & Xiaochun Yu
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Article
| Open AccessElongator mutation in mice induces neurodegeneration and ataxia-like behavior
Elp6 is a component of the Elongator complex that regulates tRNAs and translation. Here the authors identify a mutation in the Elp6 gene that contributes to the cerebellar ataxia-like phenotype in a mutant mouse.
- Marija Kojic
- , Monika Gaik
- & Brandon J. Wainwright
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Article
| Open AccessHigh-resolution visualization of H3 variants during replication reveals their controlled recycling
Epigenetic modifications are a key contributor to cell identity, and their propagation is crucial for proper development. Here the authors use a super-resolution microscopy approach to reveal how histone variants are faithfully transmitted during genome duplication, and reveal an important role for the histone chaperone ASF1 in the redistribution of parental histones.
- Camille Clément
- , Guillermo A. Orsi
- & Geneviève Almouzni
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Article
| Open AccessStructural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1
Incessant telomere synthesis in cancer cells depends on specific mutations in the TERT promoter, enabling its activation by transcription factors ETS1 and p52. Here, the authors elucidate the structural basis for p52/ETS1 binding to mutant TERT, suggesting a general mechanism for TERT reactivation in cancer.
- Xueyong Xu
- , Yinghui Li
- & Haiwei Song
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Article
| Open AccessInterphase human chromosome exhibits out of equilibrium glassy dynamics
The 3D organization of chromosomes within the nuclear space is important for biological functions. Here the authors model chromosomes as self-avoiding copolymers with distinct epigenetic states, and show that the features of experimentally generated contact maps can be reproduced and their dynamics predicted.
- Guang Shi
- , Lei Liu
- & D. Thirumalai
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Article
| Open AccessInhibition of a K9/K36 demethylase by an H3.3 point mutation found in paediatric glioblastoma
Recent studies have identified a number of oncogenic histone point mutations in different cancers. Here the authors provide evidence that H3.3 G34R substitution mutation, which is found in paediatric gliomas, causes changes in H3K9me3 and H3K36me3 by interfering with the KDM4 family of K9/K36 demethylases.
- Hsiao P. J. Voon
- , Maheshi Udugama
- & Lee H. Wong
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Article
| Open AccessEndogenous transcripts control miRNA levels and activity in mammalian cells by target-directed miRNA degradation
Via the target-directed miRNA degradation process, RNAs can induce degradation of miRNAs by binding with extensive complementarity. Here, the authors show Serpine1 mRNA as one such RNA that can control the levels of the endogenous miRNA miR-30b/c-5p by modulating miRNA degradation.
- Francesco Ghini
- , Carmela Rubolino
- & Francesco Nicassio
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Article
| Open AccessEvaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia
Chromatin accessibility may be altered in disease states. Here the authors carry out ATAC-seq on a large number of samples of dorsolateral prefrontal cortex from individuals with schizophrenia, and healthy controls.
- Julien Bryois
- , Melanie E. Garrett
- & Gregory E. Crawford
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Article
| Open AccessFunctional activity of the H3.3 histone chaperone complex HIRA requires trimerization of the HIRA subunit
The HIRA histone chaperone complex is involved in the deposition of the histone variant H3.3. Here the authors, by using biochemical and crystallographic approaches, report the homotrimerization of the HIRA subunit which is critical for the functional activity of the complex.
- Dominique Ray-Gallet
- , M. Daniel Ricketts
- & Geneviève Almouzni
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Article
| Open AccessA metabolic interplay coordinated by HLX regulates myeloid differentiation and AML through partly overlapping pathways
HLX transcription factor regulates haematopoietic stem and progenitor cell (HSPC) differentiation and is overexpressed in acute myeloid leukemia. Here the authors show that HLX overexpression leads to myeloid differentiation block in zebrafish and human HSPCs by direct regulation of metabolic pathways.
- Indre Piragyte
- , Thomas Clapes
- & Eirini Trompouki
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Article
| Open AccessAND-1 fork protection function prevents fork resection and is essential for proliferation
AND-1, the vertebrate orthologue of Ctf4, is a critical player during DNA replication and for maintenance of genome integrity. Here the authors use a conditional AND-1 depletion system in avian DT40 cells to reveal the consequences of the lack of AND-1 on cell proliferation and DNA replication.
- Takuya Abe
- , Ryotaro Kawasumi
- & Dana Branzei
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Article
| Open AccessNOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer
Splicing of the telomerase transcript, hTERT, can be altered in cancer cells. Here the authors report NOVA1, as a splicing regulator that directly interacts with hTERT pre-mRNA enhancing the number of full-length transcripts and thus telomerase activity in lung cancer cells.
- Andrew T. Ludlow
- , Mandy Sze Wong
- & Jerry W. Shay
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Article
| Open AccessTRPS1 shapes YAP/TEAD-dependent transcription in breast cancer cells
YAP is a transcriptional co-activator downstream of Hippo pathway that displays oncogenic but also tumour suppressive functions. Here, the authors perform an unbiased genome wide CRISPR screen and identify Trichorhinophalangeal syndrome 1 (TRPS1) that represses YAP/TEAD activity independently of Hippo pathway in breast cancer.
- Dana Elster
- , Marie Tollot
- & Björn von Eyss
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Article
| Open AccessGating of miRNA movement at defined cell-cell interfaces governs their impact as positional signals
Movement of small RNA between cells is critical to plant development and stress responses. Here the authors uncover a gate-keeping mechanism that can restrict small RNA movement at cell-cell interfaces, providing selectivity in long-distance signalling and limiting the scope of local mobility.
- Damianos S. Skopelitis
- , Kristine Hill
- & Marja C. P. Timmermans
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Article
| Open AccessDirected evolution of CRISPR-Cas9 to increase its specificity
Undesired off-target effects can hamper the use of CRISPR-Cas9 in therapeutic applications. Here the authors use a directed evolution approach to develop Sniper-Cas9 which combines high specificity with no loss of on-target activity.
- Jungjoon K. Lee
- , Euihwan Jeong
- & Jin-Soo Kim
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Article
| Open AccessA novel environment-evoked transcriptional signature predicts reactivity in single dentate granule neurons
Single nuclei RNA-seq has been used to characterize transcriptional signature of environment-related activity in cells of the dentate gyrus. Here the authors use this approach to show that whether a neuron will be reactivated in response to re-exposure to a previous environment can be predicted by its transcriptional signature.
- Baptiste N. Jaeger
- , Sara B. Linker
- & Fred H. Gage
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Article
| Open AccessA widespread alternate form of cap-dependent mRNA translation initiation
Binding of eIF4E to the 5′ cap of mRNAs is a key early step in canonical translation initiation, but the requirement for eIF4E is not universal. Here the authors show that the eIF4G homolog DAP5 interacts with eIF3 to promote cap-dependent translation of a significant number of mRNA in an eIF4E-independent manner.
- Columba de la Parra
- , Amanda Ernlund
- & Robert J. Schneider
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Article
| Open AccessVisualization of translation termination intermediates trapped by the Apidaecin 137 peptide during RF3-mediated recycling of RF1
In bacteria, the process of translation termination is performed by three termination release factors RF1, RF2 and RF3. Here the authors provide detailed structural insights into the mechanism by which RF1 is dissociated from the ribosome by RF3 during termination.
- Michael Graf
- , Paul Huter
- & Daniel N. Wilson
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Article
| Open AccessViral regulation of host cell biology by hijacking of the nucleolar DNA-damage response
Many RNA viruses that replicate in the cytoplasm express proteins that localize to nucleoli, but the nucleolar functions remain largely unknown. Here, the authors show that the Henipavirus matrix protein mimics an endogenous Treacle partner of the DNA-damage response, resulting in suppression of rRNA biogenesis.
- Stephen M. Rawlinson
- , Tianyue Zhao
- & Gregory W. Moseley
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Comment
| Open AccessA critical view on transgenerational epigenetic inheritance in humans
- Bernhard Horsthemke
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Article
| Open AccessLong noncoding RNA licensing of obesity-linked hepatic lipogenesis and NAFLD pathogenesis
The LXR-SREBP1c pathway promotes hepatic lipogenesis that is deregualted in fatty liver disease. Here the authors show that the long noncoding RNA Blnc1 contributes to the development of obesity-driven steatosis by enabling SREBP1c trascriptional activity in response to LXR activation.
- Xu-Yun Zhao
- , Xuelian Xiong
- & Jiandie D. Lin
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Article
| Open AccessPause sequences facilitate entry into long-lived paused states by reducing RNA polymerase transcription rates
Transcription elongation by RNA polymerase (RNAP) is interspersed with sequence-dependent pausing which is difficult to study due to spatiotemporal limitations of available methods. Here authors use a high-resolution optical tweezers assay and find that pause sites modify the dynamics of nearly all RNAP molecules.
- Ronen Gabizon
- , Antony Lee
- & Carlos J. Bustamante
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Correspondence
| Open AccessTrace N-glycans including sulphated species may originate from various plasma glycoproteins and not necessarily IgG
- Gordan Lauc
- , Frano Vučković
- & Manfred Wuhrer
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Article
| Open AccessEnhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks
Disease risk variants can exert their influence on phenotypes by altering epigenome function. Here, Pelikan et al. show that variants inducing allelic imbalance in histone marks in lymphoblastoid cell lines from lupus patients are enriched in autoimmune disease haplotypes and influence gene expression.
- Richard C. Pelikan
- , Jennifer A. Kelly
- & Patrick M. Gaffney
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Article
| Open AccessIntroduction of pathogenic mutations into the mouse Psen1 gene by Base Editor and Target-AID
CRISPR-guided cytidine deaminases, including BE3 (Base Editor 3) and Target-AID (activation-induced cytidine deaminase), can covert C:G base pairs to T:A at target site. Here, the authors generate missense mutations of mouse Psen1 gene and find BE3 has higher editing efficiency than Target-AID.
- Hiroki Sasaguri
- , Kenichi Nagata
- & Takaomi C. Saido
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Article
| Open AccessAn autophagy assay reveals the ESCRT-III component CHMP2A as a regulator of phagophore closure
During autophagy, phagophores elongate to form double-membrane vesicles but the mechanism behind their closure is unknown. Here, the authors develop an autophagy assay and find a role for the endosomal sorting complexes required for transport component CHMP2A as a phagophore closure regulator.
- Yoshinori Takahashi
- , Haiyan He
- & Hong-Gang Wang
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Article
| Open AccessPRMT5-mediated regulation of developmental myelination
Myelin-forming cells derive from oligodendrocyte progenitors. Here the authors identify histone arginine methyl-transferase PRMT5 as critical for developmental myelination by modulating the cross-talk between histone arginine methylation and lysine acetylation, to favor differentiation.
- Antonella Scaglione
- , Julia Patzig
- & Patrizia Casaccia
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Article
| Open AccessCTC1-STN1 terminates telomerase while STN1-TEN1 enables C-strand synthesis during telomere replication in colon cancer cells
The human CST complex (CTC1-STN1-TEN1) is essential for telomere homeostasis. Here the authors dissect the roles of individual CST subunits in telomere length maintenance through regulation of telomerase-mediated G-strand synthesis and DNA polymerase-mediated C-strand synthesis in colon cancer cells.
- Xuyang Feng
- , Shih-Jui Hsu
- & Carolyn M. Price
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Article
| Open AccessThe concerted roles of FANCM and Rad52 in the protection of common fragile sites
Fanconi anemia core proteins have been linked to common fragile site stability. Here the authors shed light into the role of FANCM in common fragile site protection by suppressing double-strand break formation and mitotic recombination.
- Hailong Wang
- , Shibo Li
- & Xiaohua Wu
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Article
| Open AccessA complex of C9ORF72 and p62 uses arginine methylation to eliminate stress granules by autophagy
Many Amyotrophic Lateral Sclerosis (ALS)-linked mutations cause accumulation of stress granules, and most ALS cases are caused by repeat expansions in C9ORF72. Here the authors show that C9ORF72 and the autophagy receptor p62 interact to associate with proteins symmetrically dimethylated on arginines such as FUS, to eliminate stress granules by autophagy.
- Maneka Chitiprolu
- , Chantal Jagow
- & Derrick Gibbings
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Article
| Open AccessThe replication initiation determinant protein (RepID) modulates replication by recruiting CUL4 to chromatin
RepID has previously been shown to promote origin firing. Here the authors reveal that RepID regulates replication origins via the recruitment of the CRL4 complex, and prevents re-initiation and unscheduled DNA replication.
- Sang-Min Jang
- , Ya Zhang
- & Mirit I. Aladjem
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Article
| Open AccessSingle cell transcriptome profiling of retinal ganglion cells identifies cellular subtypes
Retinal ganglion cells (RGCs) are diverse in cellular function and physiology. This study demonstrates additional RGC heterogeneity using single cell transcriptomic analyses to classify 40 classes of RGCs in early postnatal mice before eye opening.
- Bruce A. Rheaume
- , Amyeo Jereen
- & Ephraim F. Trakhtenberg
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Article
| Open AccessStromal PTEN determines mammary epithelial response to radiotherapy
The tumor microenvironment influences tumor progression. Here the authors show that lack of stromal PTEN phosphatase induces DNA repair defects in the neighboring mammary gland epithelial cells via hyperactivation of EGF-receptor signaling, resulting in higher radiation-induced DNA damage and hyperplasia.
- Gina M. Sizemore
- , Subhasree Balakrishnan
- & Michael C. Ostrowski
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Article
| Open AccessCell fate potentials and switching kinetics uncovered in a classic bistable genetic switch
Bistable switches are a common regulatory motif in cell fate decision-making circuits with two mutually exclusive expression states. Here the authors develop a bistable reporter system and report two additional expression states.
- Xiaona Fang
- , Qiong Liu
- & Jie Xiao
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Article
| Open AccessZNF506-dependent positive feedback loop regulates H2AX signaling after DNA damage
Following double-strand break a cascade of events leads to the recruitment of repair factors to damaged sites. Here the authors identify ZNF506 as a key factor that mediates post-translational modification changes in H2AX affecting the DNA damage response.
- Somaira Nowsheen
- , Khaled Aziz
- & Zhenkun Lou
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Article
| Open AccessMechanical architecture and folding of E. coli type 1 pilus domains
The pilus type 1 of uropathogenic E. coli must resist mechanical forces to remain attached to the epithelium. Here the authors use single-molecule force spectroscopy to demonstrate a hierarchy of mechanical stability among the pilus domains and show that the oxidoreductase DsbA also acts as a folding chaperone on the domains.
- Alvaro Alonso-Caballero
- , Jörg Schönfelder
- & Raul Perez-Jimenez
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Article
| Open AccessSUMO2 conjugation of PCNA facilitates chromatin remodeling to resolve transcription-replication conflicts
Transcription-replication conflicts need to be resolved to minimize genome instability. Here the authors show that SUMO2-conjugated PCNA destabilizes RNAPII from chromatin, enhances replication progression and limits transcription-induced DNA damage at common fragile sites.
- Min Li
- , Xiaohua Xu
- & Yilun Liu
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Article
| Open AccessMolecular basis for the inhibition of the methyl-lysine binding function of 53BP1 by TIRR
Tudor interacting repair regulator (TIRR) is a negative regulator of 53BP1 in DNA damage repair processes. Here the authors give mechanistic insights into how TIRR mediates suppression by solving the crystal structure of TIRR bound to the 53BP1 tandem Tudor domain (TTD).
- Jiaxu Wang
- , Zenglin Yuan
- & Xiuhua Liu
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Article
| Open AccessAnalysis of PARP inhibitor toxicity by multidimensional fluorescence microscopy reveals mechanisms of sensitivity and resistance
Methods to study anti-cancer drugs cytotoxicity are often low throughput and rely on population average. Here the authors present an automated image-based cytometry method to quantify multiple cytotoxicity parameters in single cells, and use it to study the effect of PARP inhibitors in cancer cells.
- Jone Michelena
- , Aleksandra Lezaja
- & Matthias Altmeyer
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Article
| Open AccessmiR-103 promotes endothelial maladaptation by targeting lncWDR59
MicroRNAs play important roles in endothelial cells injury, proliferation and maladaptation by negatively regulating posttranscriptional gene expression. Here the authors uncover the role of the long non coding RNA lncWDR59, target of miR-103, in endothelial maladaptation.
- Lucia Natarelli
- , Claudia Geißler
- & Andreas Schober
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Article
| Open AccessHuman pluripotent reprogramming with CRISPR activators
CRISPRa is an attractive tool for cellular reprogramming due to its multiplexing capacity and direct targeting of genomic loci. Here the authors demonstrate the reprogramming of human fibroblasts into iPSCs, which is enhanced by targeting a conserved Alu-motif.
- Jere Weltner
- , Diego Balboa
- & Timo Otonkoski
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Article
| Open AccessEngineering circular RNA for potent and stable translation in eukaryotic cells
Circular RNAs have recently been shown to have protein-coding potential. Here the authors design a self-splicing RNA that, when circularized, provides for stable high-yield protein production.
- R. Alexander Wesselhoeft
- , Piotr S. Kowalski
- & Daniel G. Anderson
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- Cell division
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- DNA metabolism
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- Epigenetics
- Non-coding RNAs
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- Post-translational modifications
- Protein folding
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