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| Open AccessThe single-cell transcriptomic atlas and RORA-mediated 3D epigenomic remodeling in driving corneal epithelial differentiation
Ocular homeostasis and vision depend on the differentiation of limbal stem/progenitor cells into corneal epithelial cells. Here, the authors report transcriptional dynamics and RORA-mediated epigenetic remodeling underlying the differentiation of human corneal epithelium.
- Mingsen Li
- , Huizhen Guo
- & Hong Ouyang
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Article
| Open AccessSystems-based identification of the Hippo pathway for promoting fibrotic mesenchymal differentiation in systemic sclerosis
Systemic sclerosis (SSc) is an autoimmune disease causing skin fibrosis and organ inflammation. Here the authors generate and analyze SSc skin single cell RNA sequencing data to propose contributions from both myofibroblasts and endothelial-to-mesenchymal -transitioning cells (EndoMT) to skin fibrosis, and to implicate the involvement of Hippo signaling pathways.
- Feiyang Ma
- , Pei-Suen Tsou
- & Johann E. Gudjonsson
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Article
| Open AccessHistone lactylation couples cellular metabolism with developmental gene regulatory networks
While metabolic reprogramming has been shown to drive changes in cell identity, the link between cellular metabolism and gene expression remains poorly characterized. Here they show that histone lactylation couples metabolism and transcription during neural crest cell differentiation in the early embryo.
- Fjodor Merkuri
- , Megan Rothstein
- & Marcos Simoes-Costa
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Article
| Open AccessMapping nucleosome-resolution chromatin organization and enhancer-promoter loops in plants using Micro-C-XL
The authors employ Micro-C-XL to investigate chromatin structures in plants, specifically focusing on nucleosome-resolution chromatin organizations and enhancer-promoter chromatin loops in Arabidopsis, rice, and soybean.
- Linhua Sun
- , Jingru Zhou
- & Hang He
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Article
| Open AccessMutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response
Here the authors show that gain-of-function mutant p53s predispose cells to chromosomal instability by targeting MCMs, leading to activation of a cGAS-STING-non-canonical NF-κB signaling that promotes tumor metastasis and immunosuppression.
- Mei Zhao
- , Tianxiao Wang
- & Ge Zhou
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Article
| Open AccessAspergillus fumigatus mitogen-activated protein kinase MpkA is involved in gliotoxin production and self-protection
Aspergillus fumigatus produces the mycotoxin gliotoxin which is important for virulence. Here, de Castro et al characterise how excess production and subsequent fungal toxicity is controlled by the mitogen-activated protein kinase MpkA.
- Patrícia Alves de Castro
- , Camila Figueiredo Pinzan
- & Gustavo H. Goldman
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Article
| Open AccessQuantifying negative selection in human 3ʹ UTRs uncovers constrained targets of RNA-binding proteins
Identifying functional genetic variants in non-coding regions of the human genome is challenging. Here the authors apply their iMAPS approach to 3ʹ untranslated regions, identifying thousands of variants that disrupt post-transcriptional gene regulation.
- Scott D. Findlay
- , Lindsay Romo
- & Christopher B. Burge
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Article
| Open AccessRole of UPF1-LIN28A interaction during early differentiation of pluripotent stem cells
UPF1 and LIN28A are RNA-binding proteins involved in post-transcriptional regulation and cell differentiation. Here, authors report that they interact with each other via specific domains and regulate ectodermal specialization of human pluripotent stem cells.
- Seungwon Jung
- , Seung Hwan Ko
- & Jungwook Hwang
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Article
| Open AccessPrimase promotes the competition between transcription and replication on the same template strand resulting in DNA damage
Resolving R-loops caused by transcription-replication conflicts (TRCs) is vital to genome stability in organisms. Here, the authors show that the chloroplast-localized primase ATH intensifies template strand competition and exacerbates the Head-On TRCs induced DNA damage.
- Weifeng Zhang
- , Zhuo Yang
- & Qianwen Sun
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Article
| Open AccessStabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells
Post-translational modifications including protein sumoylation is under specific regulation in glioma stem cells (GSCs). Here, the authors show that Pin1 is deubiquitinated and stabilized by USP34, which in turn promotes isomerization of Ubc9, leading to SUMO1-modified global hypersumoylation to maintain the tumorigenic capacity of GSCs.
- Qiuhong Zhu
- , Panpan Liang
- & Wenchao Zhou
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Article
| Open AccessCell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions
Here, the authors show how the histone methyltransferase SETDB1 is involved in cell-type specific regulation of chromatin landscape by catalyzing H3K9me3, which antagonizes CTCF binding. They further define the subsequent transcriptomic impact.
- Phoebe Lut Fei Tam
- , Ming Fung Cheung
- & Danny Leung
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Article
| Open AccessStructural basis for DNA proofreading
Here, the authors use cryo-EM to capture nine intermediates along the DNA proofreading pathway using human mitochondrial DNA Polymerase Gamma. The results provide a step-by-step view of the DNA proofreading at single-nucleotide resolution.
- Gina Buchel
- , Ashok R. Nayak
- & Dmitry Temiakov
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Article
| Open AccessUnraveling the causal genes and transcriptomic determinants of human telomere length
Variation in human telomere length has been well studied, but most previous studies have used adult telomere length. Here, the authors explore the genetic basis of telomere length in the placenta and find suggestive causal genes modulating human telomere length.
- Ying Chang
- , Yao Zhou
- & Dandan Huang
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Article
| Open AccessThe Mycobacterium tuberculosis methyltransferase Rv2067c manipulates host epigenetic programming to promote its own survival
Singh et al. show how the M. tuberculosis methyltransferase Rv2067c outsmarts host epigenetic machinery by methylating histone H3 prior to its assembly into nucleosomes, thereby ensuring the pathogen’s intracellular survival/success.
- Prakruti R. Singh
- , Venkatareddy Dadireddy
- & Valakunja Nagaraja
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Article
| Open AccessJOINTLY: interpretable joint clustering of single-cell transcriptomes
Batch integration is a critical yet challenging step in many single-cell RNA-seq analysis workflows. Here, authors present JOINTLY, a hybrid linear and non-linear NMF-based algorithm, providing interpretable and robust cell clustering against over-integration.
- Andreas Fønss Møller
- & Jesper Grud Skat Madsen
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Article
| Open AccessBuilding synthetic chromosomes from natural DNA
Building synthetic chromosomes from natural components is an unexplored alternative to de novo chromosome synthesis that may have many potential applications. In this paper, the authors report CReATiNG, a method for constructing synthetic chromosomes from natural components in yeast.
- Alessandro L. V. Coradini
- , Christopher Ne Ville
- & Ian M. Ehrenreich
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Article
| Open AccessRBFOX2 deregulation promotes pancreatic cancer progression and metastasis through alternative splicing
The role of alternative splicing in pancreatic cancer (PDAC) development remains to be explored. Here, RBFOX2 is shown to regulate exon splicing events in transcripts encoding proteins involved in cytoskeletal remodelling programs and its downregulation promotes PDAC progression and liver metastasis.
- Michelle Maurin
- , Mohammadreza Ranjouri
- & Karen M. Mann
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Article
| Open AccessiMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis
DNA double-strand breaks (DSBs) are highly mutagenic making them central to many pathologies. Here, the authors developed a highly sensitive sequencing approach to study DSB mutagenesis, yielding insights into mutagenic outcomes and characterising their underlying mechanisms.
- Aldo S. Bader
- & Martin Bushell
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Article
| Open AccessMutant GGGGCC RNA prevents YY1 from binding to Fuzzy promoter which stimulates Wnt/β-catenin pathway in C9ALS/FTD
Intronic GGGGCC repeat expansion in the C9orf72 gene causes ALS/FTD. Here the authors show that mutant GGGGCC RNA triggers YY1-Fuzzy transcriptional dysregulation which subsequently induces Wnt/β-catenin pathway and activates cell death in C9ALS/FTD.
- Zhefan Stephen Chen
- , Mingxi Ou
- & Ho Yin Edwin Chan
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Article
| Open AccessAutophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury
Understanding the role of GPX4 in cell ferroptosis at the interface of the inner cortex and medulla is crucial in the context of renal injury. Here, the authors demonstrate that the OTUD5 interaction with GPX4 is key in resisting ischemia/reperfusion-induced ferroptosis in renal cells, offering a new strategy for treating acute kidney injury.
- Li-Kai Chu
- , Xu Cao
- & Jun Liu
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| Open AccessDissecting the genetic landscape of GPCR signaling through phenotypic profiling in C. elegans
To overcome challenges posted by vast number of GPCR genes and redundancy, the authors disrupted nearly all GPCR-encoding genes in C. elegans, enabling effective examination of GPCR signaling and offering a valuable resource for the research community.
- Longjun Pu
- , Jing Wang
- & Changchun Chen
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Article
| Open AccessAcetylation is required for full activation of the NLRP3 inflammasome
The NLRP3 inflammasome is activated in two steps, priming and assembly, in response to endogenous, microbial, and other environmental danger signals. Here authors show that the assembly step is regulated by acetylation, and inhibition of this post-translational modification prevents full activation of the inflammasome.
- Yening Zhang
- , Ling Luo
- & Kai Zhao
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Article
| Open AccessPAX3-FOXO1 uses its activation domain to recruit CBP/P300 and shape RNA Pol2 cluster distribution
Different processes are in place to facilitate RNA-Polymerase 2 (Pol2) binding to chromatin. Here the authors reveal that the fusion transcription factor PAX3-FOXO1 shapes RNA Pol2 enhancer loops by recruitment of the histone acetyltransferase p300 via a small alpha-helical hook in its activation domain. Degradation of PAX3-FOXO1 or p300 rapidly collapses Pol2 clusters.
- Yaw Asante
- , Katharina Benischke
- & Marco Wachtel
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| Open AccessMYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting
SKP2 is an oncogenic E3-ubiquitin ligase. Here the authors show that SKP2 is epigenetically regulated by the muscle lineage transcription factor MYOD, supports tumorigenesis in the Fusion Negative (FN) subtype of rhabdomyosarcoma (RMS) and impairs differentiation promoting degradation of p57Kip2.
- Silvia Pomella
- , Matteo Cassandri
- & Rossella Rota
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Article
| Open AccessProfiling ubiquitin signalling with UBIMAX reveals DNA damage- and SCFβ-Trcp1-dependent ubiquitylation of the actin-organizing protein Dbn1
Using Xenopus egg extracts, the authors developed a mass spectrometry method (UBIMAX) to identify proteins ubiquitylated in response to defined DNA lesions. Highlighting UBIMAX’s versatility, they describe the ubiquitylation of the actin regulator Dbn1 in response to DNA double-strand breaks.
- Camilla S. Colding-Christensen
- , Ellen S. Kakulidis
- & Michael L. Nielsen
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Article
| Open AccessUbiquitination-mediated Golgi-to-endosome sorting determines the toxin-antidote duality of fission yeast wtf meiotic drivers
Meiotic drivers of the wtf family kill progeny lacking the driver by producing a toxin and an antidote. Here, authors reveal that ubiquitination-mediated sorting of the antidote prevents it from becoming toxic and enables it to neutralize the toxin.
- Jin-Xin Zheng
- , Tong-Yang Du
- & Li-Lin Du
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Article
| Open AccessOn the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging
Tryptophan metabolism through the kynurenine pathway changes with age and represents a potential intervention target for age associated disease. Here, the authors show that elevating physiological levels of the kynurenine pathway metabolite 3- hydroxyanthranilic acid can promote healthy aging.
- Hope Dang
- , Raul Castro-Portuguez
- & George L. Sutphin
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Article
| Open AccessERK2-topoisomerase II regulatory axis is important for gene activation in immediate early genes
Topoisomerase II (TOP2) has been identified as one of the regulators for the transcriptional activation of immediate early genes IEGs. Here the authors report that ERK1 and ERK2 oppositely regulate transcription and ERK2 regulates TOP2B-DNA interaction and catalysis to favor IEG transcription.
- Heeyoun Bunch
- , Deukyeong Kim
- & Shun-ichi Sekine
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Article
| Open AccessMolecular basis for proofreading by the unique exonuclease domain of Family-D DNA polymerases
Family D replicative DNA polymerases (PolD) contain a unique proofreading active site. Here, the authors present structures of PolD and enzymatic studies, revealing an unanticipated correction mechanism that extends the repertoire of protein domains known to be involved in DNA proofreading.
- Leonardo Betancurt-Anzola
- , Markel Martínez-Carranza
- & Ludovic Sauguet
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Article
| Open AccessThe bacterial replication origin BUS promotes nucleobase capture
Here, the authors show that a DnaA:origin complex promotes specific nucleobase capture from a single DNA strand. It is proposed that this mechanism may play a key role stimulating opening of bacterial chromosome origins.
- Simone Pelliciari
- , Salomé Bodet-Lefèvre
- & Heath Murray
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Article
| Open AccessRemodeling of the ribosomal quality control and integrated stress response by viral ubiquitin deconjugases
Here, the authors show how the vDUB from the large tegument protein from the human herpes virus can reprogram translation in host cells by modulating the activity of the ribosome quality machinery and activating the integrated stress response.
- Jiangnan Liu
- , Noemi Nagy
- & Maria G. Masucci
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Article
| Open AccessNuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation
Zhen and colleagues show that nuclear cGAS represses L1 retrotransposition to stabilize the genome by enhancing the interaction between ORF2p and the E3 ligase TRIM41 upon DNA damage, which leads to the ubiquitination and degradation of ORF2p.
- Zhengyi Zhen
- , Yu Chen
- & Zhiyong Mao
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Article
| Open Access5mC modification orchestrates choriogenesis and fertilization by preventing prolonged ftz-f1 expression
The mechanism by which DNA methylation regulates female reproduction in insects is largely unknown. Here Zhao et al. demonstrate that the 5mC modification orchestrates timely choriogenesis and proper fertilization by preventing prolonged ftz-f1 expression in the German cockroach.
- Zheng Zhao
- , Liang Li
- & Chonghua Ren
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Article
| Open AccessThe assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination
The role that cellular bioenergetics plays in the early stages of Alzheimer’s disease is poorly understood. Here the authors describe structures of key OXPHOS assembly proteins, providing insights into how these pathways are interlinked and regulated.
- Lindsay McGregor
- , Samira Acajjaoui
- & Montserrat Soler-Lopez
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Article
| Open AccessImmunoproximity biotinylation reveals the axon initial segment proteome
The molecular composition of the axon initial segment (AIS) is not well defined. Here, the authors used a ratiometric immunoproximity labeling strategy on fixed wild-type rat neurons to identify the AIS proteome, including the scaffolding protein SCRIB.
- Wei Zhang
- , Yu Fu
- & Peng Zou
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Article
| Open AccessAn allele-selective inter-chromosomal protein bridge supports monogenic antigen expression in the African trypanosome
Nuclear organization impacts allelic exclusion. Here, the authors describe a self-limiting protein bridge that connects two chromosomes, and two transcription and splicing compartments, to maintain monogenic VSG expression in the African trypanosome.
- Joana R. C. Faria
- , Michele Tinti
- & David Horn
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Article
| Open AccessDissecting the basis for differential substrate specificity of ADAR1 and ADAR2
Human ADAR1 and ADAR2 edit millions of adenosines transcriptome-wide, altering RNA structure. Here the authors show that variations in RNA binding domains influence site-specific editing, enhancing ADAR2-targeted therapeutics.
- Marlon S. Zambrano-Mila
- , Monika Witzenberger
- & Schraga Schwartz
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Article
| Open AccessPhase-separated CCER1 coordinates the histone-to-protamine transition and male fertility
Here the authors reveal that phase‐separated nuclear CCER1 condensates are required for male fertility by mediating chromatin condensation and histone epigenetic modification, while loss‐of‐function variants of human CCER1 are pathogenic in patients with nonobstructive azoospermia (NOA).
- Dongdong Qin
- , Yayun Gu
- & Zhibin Hu
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Article
| Open AccessRIF1 regulates early replication timing in murine B cells
Here the authors show that in activated B cells, RIF1 primarily binds early-replicating active chromatin and promotes early replication. RIF1 and MCM proteins establish early replication timing signatures genome-wide and ensure early replication of highly transcribed genes.
- Daniel Malzl
- , Mihaela Peycheva
- & Rushad Pavri
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Article
| Open AccessThe distinct translational landscapes of gram-negative Salmonella and gram-positive Listeria
In this work, Bryant and Lastovka et al. utilise advanced ribosome profiling and transcriptomics techniques, to reveal distinct translation control mechanisms in Salmonella and Listeria, two highly divergent bacterial species.
- Owain J. Bryant
- , Filip Lastovka
- & Betty Y. -W. Chung
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Article
| Open AccessLoss of cohesin regulator PDS5A reveals repressive role of Polycomb loops
Through a genetic screen, the authors find that the cohesin regulator PDS5A is required for Polycomb target gene silencing. Derepression upon cohesin dysregulation is linked to loss of Polycomb loops without change in repressive chromatin domains.
- Daniel Bsteh
- , Hagar F. Moussa
- & Oliver Bell
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Article
| Open AccessThe long non-coding RNA HOTAIR contributes to joint-specific gene expression in rheumatoid arthritis
Although patients with rheumatoid arthritis (RA) usually exhibit symmetrical joint involvement, some can develop alternative patterns of arthritis, often translating into differences in responsiveness to treatment. In this study, the authors propose that the long-noncoding RNA, HOTAIR, might contribute to these differences.
- Muriel Elhai
- , Raphael Micheroli
- & Caroline Ospelt
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Article
| Open AccessSingle cell multi-omics reveal intra-cell-line heterogeneity across human cancer cell lines
Intra-cell line heterogeneity remains to be characterized. Here, the use of single multi-omics on a large panel of human cell lines identifies copy number variation, epigenetic variation and extrachromosomal DNA distribution as the main contributors to intra-cell line heterogeneity.
- Qionghua Zhu
- , Xin Zhao
- & Liang Wu
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Article
| Open AccessStructure of the complete Saccharomyces cerevisiae Rpd3S-nucleosome complex
In this study, the authors present the cryogenic electron microscopy reconstruction of the Rpd3S complex engaged with a nucleosome. The corresponding model describes the interactions that facilitate histone deacetylation within gene bodies by the Rpd3S complex.
- Jonathan W. Markert
- , Seychelle M. Vos
- & Lucas Farnung
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Article
| Open AccessLncRNA MIR200CHG inhibits EMT in gastric cancer by stabilizing miR-200c from target-directed miRNA degradation
The roles of long non-coding RNAs (lncRNAs) in different subtypes of gastric cancer (GC) remain to be characterized. Here, the authors identify lncRNA MIR200CHG as a master regulator of Microsatellite stable (MSS)/epithelial-mesenchymal transition (EMT) GC subtype, which inhibits EMT and metastasis by stabilizing miR-200c.
- Yixiao Zhu
- , Chengmei Huang
- & Xin Wang
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Article
| Open AccessThe separation pin distinguishes the pro– and anti–recombinogenic functions of Saccharomyces cerevisiae Srs2
Here the authors report that the main role of the protein Srs2 in homologous recombination is to remove Rad51 from single stranded DNA, rather than to drive synthesis-dependent strand annealing.
- Aviv Meir
- , Vivek B. Raina
- & Eric C. Greene
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Article
| Open AccessExcess PrPC inhibits muscle cell differentiation via miRNA-enhanced liquid–liquid phase separation implicated in myopathy
The prion protein PrPC is known to play a role in skeletal muscle development and physiology, including in myopathy. Here, the authors report that excess PrPC binds microRNAs that enhance its aggregation, which inhibits autophagy in muscle cells.
- Jing Tao
- , Yanping Zeng
- & Yi Liang
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Article
| Open AccessCharacterization of nucleolar SUMO isopeptidases unveils a general p53-independent checkpoint of impaired ribosome biogenesis
Ribosome biogenesis is tightly coordinated with cell-cycle progression. By characterizing the SUMO isopeptidases SENP3/SENP5, Doenig et al. identify a long-sought p53-independent impaired ribosome checkpoint that converges on downregulation of CDK6.
- Judith Dönig
- , Hannah Mende
- & Stefan Müller
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Article
| Open AccessIn vivo RNA interactome profiling reveals 3’UTR-processed small RNA targeting a central regulatory hub
Here the authors report a new approach to profile RNA-RNA interactions in live bacterial cells. The charted RNA interaction networks unveil a key mRNA regulatory hub targeted by twelve small RNAs, including a novel RNA involved in fatty acid metabolism.
- Fang Liu
- , Ziying Chen
- & Yanjie Chao
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