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Article
| Open Accessp53 promotes revival stem cells in the regenerating intestine after severe radiation injury
The tumor suppressor p53 is the guardian of the genome. Here, the authors use comprehensive approaches to demonstrate that transient p53 activity induces revival stem cells to promote the regeneration of severely irradiated intestinal epithelium in mice.
- Clara Morral
- , Arshad Ayyaz
- & David G. Kirsch
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Article
| Open AccessAccelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation
Here the authors find that erythroblasts of myelodysplastic syndromes with SF3B1 mutation leading to inefficient erythropoiesis show DNA replication stress with accelerated forks and reduced R-loops. Restoring R-loops by a histone deacetylase inhibitor rescues erythroid differentiation.
- David Rombaut
- , Carine Lefèvre
- & Michaela Fontenay
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Article
| Open AccessSystematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis
Authors perform an in vivo mass spectrometry-based interactome analysis of HOIL-1-interacting protein, a key component of linear ubiquitination assembly complex.
- Yesheng Fu
- , Lei Li
- & Lingqiang Zhang
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Article
| Open AccessSeeding the meiotic DNA break machinery and initiating recombination on chromosome axes
Meiotic cells deliberately break their DNA to allow chromosomes to swap genetic material. Here, authors reveal genetically separable pathways controlling the seeding and growth of chromosome-bound protein condensates responsible for DNA breaks.
- Ihsan Dereli
- , Vladyslav Telychko
- & Attila Tóth
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Article
| Open AccessNon-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells
DNA methylation is an essential epigenetic mark in mammals. The maintenance of this mark relies on two key proteins: DNMT1 and UHRF1. Here the authors show that, beyond activating DNMT1, UHRF1 has crucial regulatory functions in cancer cells.
- Kosuke Yamaguchi
- , Xiaoying Chen
- & Pierre-Antoine Defossez
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Article
| Open AccessTranslation velocity determines the efficacy of engineered suppressor tRNAs on pathogenic nonsense mutations
An emerging therapeutic strategy is to suppress nonsense mutations with engineered suppressor tRNAs. Here, the authors show that the mRNA translation velocity is a key parameter determining the efficacy of suppressor tRNAs.
- Nikhil Bharti
- , Leonardo Santos
- & Zoya Ignatova
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Article
| Open AccessStatins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1
Endothelial dysfunction has been shown to occur in HFpEF and we know that statins can target endothelial dysfunction by inhibiting miR-133a. Here the authors show that statins improve diastolic dysfunction in HFpEF by increasing the levels of a circRNA which, in turns, binds to miR-133a modulating its downstream targets.
- Bin Li
- , Wen-Wu Bai
- & Shuang-Xi Wang
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Article
| Open AccessThe CRISPR-Cas13a Gemini System for noncontiguous target RNA activation
CRISPR-Cas13a based methods currently use contiguous target RNA activation, which only enables single-target detection or editing. Here the authors propose a noncontiguous target RNA activation approach which can provide rapid, simultaneous and sensitive detection of two RNAs in a single readout, as well as parallel dual transgene knockdown.
- Hongrui Zhao
- , Yan Sheng
- & Jiaming Hu
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Article
| Open AccessDbf4-dependent kinase promotes cell cycle controlled resection of DNA double-strand breaks and repair by homologous recombination
The repair of DNA double strand breaks is strictly controlled during the cell cycle by the CDK kinase. Here the authors identify the DDK kinase as a second major regulator for this cell cycle regulation and elucidate its functional targets.
- Lorenzo Galanti
- , Martina Peritore
- & Boris Pfander
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Article
| Open AccessLoss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment
CREBBP and KMT2D mutations frequently co-occur in B cell lymphomas with unclear significance. Here the authors show that they cooperate to skew B cell fate decisions and induce a CD8-depleted immune-evasive microenvironment to facilitate lymphomagenesis.
- Jie Li
- , Christopher R. Chin
- & Ari M. Melnick
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Article
| Open AccessCold-induced FOXO1 nuclear transport aids cold survival and tissue storage
How tissues adapt to extreme cold is not well understood. Here, the authors discover a mechanism that promotes FOXO1-mediated cold survival gene transcription at low temperatures, with potential implications for long-term tissue storage for transplantation.
- Xiaomei Zhang
- , Lihao Ge
- & Jingxing Ou
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Article
| Open AccessPatchy and widespread distribution of bacterial translation arrest peptides associated with the protein localization machinery
Regulatory arrest peptides interact with the bacterial ribosome to halt their own translation. Here, Fujiwara et al. analyse thousands of bacterial genome sequences and identify additional arrest peptides, revealing sequence diversity and patchy, but widespread, distribution across the bacterial domain.
- Keigo Fujiwara
- , Naoko Tsuji
- & Shinobu Chiba
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Article
| Open AccessPARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress
Here the authors show that PARP2 drives telomere fragility by orchestrating the Break-induced replication (BIR) pathway. This promotes DNA end resection and DNA synthesis via the regulation of POLD3.
- Daniela Muoio
- , Natalie Laspata
- & Elise Fouquerel
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Article
| Open AccessInvolution of brown adipose tissue through a Syntaxin 4 dependent pyroptosis pathway
Aging, chronic high-fat diet feeding, or housing at thermoneutrality induces brown adipose tissue (BAT) involution. Here, the authors demonstrate that physiologic aging induced involution and thermogenic dysfunction result from pyroptotic signalling activation.
- Xiaofan Yu
- , Gabrielle Benitez
- & Daorong Feng
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Article
| Open AccessLoss-of-function mutation in PRMT9 causes abnormal synapse development by dysregulation of RNA alternative splicing
Mutations in protein arginine methyltransferase 9 (PRMT9) are linked to intellectual disability. Here, the authors show that mutant PRMT9 fails to methylate its primary substrate SF3B2, causing aberrant RNA splicing and abnormal synapse development.
- Lei Shen
- , Xiaokuang Ma
- & Yanzhong Yang
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Article
| Open AccessThe PTM profiling of CTCF reveals the regulation of 3D chromatin structure by O-GlcNAcylation
CTCF, which is known to play critical role in chromatin structure, undergoes post-translational modifications (PTMs). In this research, O-GlcNAcylation was found to inhibit CTCF binding, impacting 3D chromatin structure, gene expression and cellular development.
- Xiuxiao Tang
- , Pengguihang Zeng
- & Junjun Ding
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Article
| Open AccessSystematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma
Proteomic, transcriptomic, and genomic analysis has shown osteosarcoma (OS) to be a complex and heterogenous disease but revealed little about its carcinogenesis or potential therapeutic targets. Here, the authors profile the RNA interactome, transcriptome and proteome of cells derived from OS patients, identifying a targetable vulnerability to translation inhibition.
- Yang Zhou
- , Partho Sarothi Ray
- & Andreas E. Kulozik
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Article
| Open Accessp53 rapidly restructures 3D chromatin organization to trigger a transcriptional response
Here the authors uncover p53’s role as the master regulator of spatio-temporal genome organization. p53 controls the expression of 340 distal genes through newly formed and pre-existing loops between p53-bound enhancers and promoters.
- François Serra
- , Andrea Nieto-Aliseda
- & Biola M. Javierre
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Article
| Open AccessA lineage-resolved cartography of microRNA promoter activity in C. elegans empowers multidimensional developmental analysis
By tracing promoter expression in lineage-mapped single cells, Xu et al. present a whole-body cartography of microRNA transcriptional activities during C. elegans embryogenesis and demonstrate its broad utility in multifaceted functional analyses.
- Weina Xu
- , Jinyi Liu
- & Zhuo Du
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Article
| Open AccessTranscription-driven DNA supercoiling counteracts H-NS-mediated gene silencing in bacterial chromatin
Proteins compacting the bacterial chromosome obstruct transcription and must be transiently displaced to allow gene expression. Here, the authors show that the bacterial nucleoid structuring protein H-NS can be dislodged, from a distance, by the twisting in the DNA generated ahead of approaching RNA polymerase.
- Nara Figueroa-Bossi
- , Rocío Fernández-Fernández
- & Lionello Bossi
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Article
| Open AccessA rapid inducible RNA decay system reveals fast mRNA decay in P-bodies
Studying RNA decay remains a challenging task. Here, the authors present a technology that enables inducible rapid degradation of targeted mRNAs. Visualizing mRNA decay dynamics unveils insights into P-body function in RNA metabolism.
- Lauren A. Blake
- , Leslie Watkins
- & Bin Wu
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Article
| Open AccessMitochondrial H2O2 release does not directly cause damage to chromosomal DNA
Nuclear DNA damage downstream of mitochondrial ROS is often cited to contribute to cancer initiation and aging. However, here the authors show that although H2O2 induces DNA mutations when produced near DNA, it does not when released by mitochondria.
- Daan M. K. van Soest
- , Paulien E. Polderman
- & Tobias B. Dansen
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Article
| Open AccessCondensin-mediated restriction of retrotransposable elements facilitates brain development in Drosophila melanogaster
Mutations in condensin subunits cause microcephaly, but the underlying molecular mechanisms remain elusive. Here, the authors show that unrestricted retrotransposable element activity impairs brain development in condensin insufficient organisms.
- Bert I. Crawford
- , Mary Jo Talley
- & Michelle S. Longworth
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Article
| Open AccessReal-time monitoring of replication errors’ fate reveals the origin and dynamics of spontaneous mutations
An interdisciplinary approach following replication errors in Escherichia coli unveils that many spontaneous mutations originate from inefficient repair, and that repair capacity is variable between single cells within a bacterial population.
- Chiara Enrico Bena
- , Jean Ollion
- & Marina Elez
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Article
| Open AccessSynaptically-targeted long non-coding RNA SLAMR promotes structural plasticity by increasing translation and CaMKII activity
Long noncoding RNAs (lncRNAs) function in many processes yet their participation in learning is largely unknown. Here, we identify and characterize the lncRNA SLAMR, which is recruited to stimulated synapses to mediate structural plasticity during experience and fear memory consolidation.
- Isabel Espadas
- , Jenna L. Wingfield
- & Sathyanarayanan Puthanveettil
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Article
| Open AccessProfiling the colonic mucosal response to fecal microbiota transplantation identifies a role for GBP5 in colitis in humans and mice
Faecal microbiota transplantation (FMT) can be used to treat established colitis. Here the authors profile transcriptional changes in humans after FMT and how this relates to colitis remission identifying a role for GBP5, and this protein is validated in a loss-of-function mouse model.
- Laurence D. W. Luu
- , Abhimanu Pandey
- & Nadeem O. Kaakoush
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Article
| Open AccessPrecise prediction of phase-separation key residues by machine learning
Understanding intracellular phase separation is essential for transcriptional control, cell fate, and disease. Here the authors report PSPHunter which accurately predicts key residues, aiding in disease-associated protein identification and mechanistic insights.
- Jun Sun
- , Jiale Qu
- & Junjun Ding
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Article
| Open AccessDiverging co-translational protein complex assembly pathways are governed by interface energy distribution
Protein complex assembly can occur co-translationally. Here, the authors uncover diverging assembly pathways and hotspot disruptions in N-terminal acetyltransferases, enzymes implicated in neurodegenerative diseases. Their model predicts co-translational assembly based on interface energy distribution.
- Johannes Venezian
- , Hagit Bar-Yosef
- & Ayala Shiber
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Article
| Open AccessFunctional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair
Here the authors describe a functional screening platform in human stem cells to identify and optimize protein-based gene editing additives that increase homologous directed recombination and have potential to improve gene therapy workflows.
- Juan A. Perez-Bermejo
- , Oghene Efagene
- & Kristen L. Seim
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Article
| Open AccessFANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells
Here the authors show that PARPi efficacy along with the fitness of BRCA1 deficient cells relies on FANCJ, which maintains S-phase PARP1 activity by preventing its sequestration with MSH2 on G-quadruplexes.
- Ke Cong
- , Nathan MacGilvary
- & Sharon B. Cantor
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Article
| Open AccessDevelopmental progression of DNA double-strand break repair deciphered by a single-allele resolution mutation classifier
DNA double-strand breaks (DSBs) are repaired by a hierarchically regulated network of pathways. Here, authors develop ICP for deciphering somatic DSB repair patterns in multicellular organisms and discover developmental regulation in flies and mosquitoes, enabling tracking of mutant alleles and interhomolog copying of gene cassettes.
- Zhiqian Li
- , Lang You
- & Ethan Bier
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Article
| Open AccessIon mobility-tandem mass spectrometry of mucin-type O-glycans
Currently, only a few specialized labs can characterize O-glycans. The present study couples high-resolution ion mobility spectrometry with tandem mass spectrometry to efficiently identify complex O-glycan structures in clinical samples.
- Leïla Bechtella
- , Jin Chunsheng
- & Kevin Pagel
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Article
| Open AccessStructure of the human Bre1 complex bound to the nucleosome
The structure of the nucleosome-bound human Bre1 complex reveals that its two RING domains bind the acidic patch and nucleosomal DNA, directing the E2 enzyme and ubiquitin for H2BK120-specific ubiquitination. The binding mode suggests a possible regulatory mechanism through nucleosomal DNA flexibility.
- Shuhei Onishi
- , Kotone Uchiyama
- & Toru Sengoku
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Article
| Open AccessThe aldehyde dehydrogenase 2 rs671 variant enhances amyloid β pathology
Here, Wang et al. report that the ALDH2 rs671 variant exacerbates amyloid-β pathology in the human brain. Mechanistically, the variant leads to 4-HNE accumulation, adducting Lys53 of C99 and promoting the production of Aβ40.
- Xia Wang
- , Jiayu Wang
- & Wei Ge
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Article
| Open AccessDiindoles produced from commensal microbiota metabolites function as endogenous CAR/Nr1i3 ligands
Here, combining metabolomic, proteomic and biophysical analyses, the authors identify and characterize a series of diindole molecules produced from commensal bacteria metabolites that act as specific agonists for the orphan constitutive androstane receptor (CAR), having potential to modulate gut and liver inflammation, metabolic diseases and cancer.
- Jiabao Liu
- , Ainaz Malekoltojari
- & Henry M. Krause
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Article
| Open AccessBET inhibitors drive Natural Killer activation in non-small cell lung cancer via BRD4 and SMAD3
Combination of BET inhibitors (BETi) with immunotherapy has been reported to be synergic for the treatment of non-small cell lung carcinoma (NSCLC). Here, the authors show that BETi-induced epigenetic reprogramming downregulates the expression of NK cell inhibitory receptors on NK cells, increasing their activation and cytotoxicity against NSCLC.
- Francesca Reggiani
- , Giovanna Talarico
- & Valentina Sancisi
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Article
| Open AccessGAS41 modulates ferroptosis by anchoring NRF2 on chromatin
GAS41 is recognized as a histone reader and oncogene, but the mechanism by which GAS41 contributes to tumorigenesis is not well understood. Here, the authors discover that GAS41 is a ferroptosis repressor that anchors NRF2 to chromatin, promoting tumor growth.
- Zhe Wang
- , Xin Yang
- & Wei Gu
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Article
| Open Accessp53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice
DNA repair deficiency can cause tissue-specific phenotypes in humans and mice. Here, the authors find that p53 drives different, but tissue-specific responses despite the same defect in DNA repair. p53 drives blood stem cell loss but restrains liver polyploidisation in the absence of Ercc1.
- Ross J. Hill
- , Nazareno Bona
- & Gerry P. Crossan
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Article
| Open AccessReciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer
TP63 is a master regulator transcription factor in squamous cell carcinomas (SCCs). Here the authors report that TP63 suppresses IFNγ signaling in SCC tumors and that its inhibition is associated with enhanced anti-tumor immunity and response to anti-PD1.
- Yuan Jiang
- , Yueyuan Zheng
- & Yan-Yi Jiang
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Article
| Open AccessCombined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer
The MAPK pathway is an important therapeutic target in pancreatic ductal adenocarcinoma (PDAC), but success is limited by pathway reactivation, which drives resistance. Here, the authors investigate the mechanism underlying HER2-reactivation post KRAS-MAPK inhibition, identifying combination of MAPK and HER2 inhibition as a therapeutic strategy.
- Ashenafi Bulle
- , Peng Liu
- & Kian-Huat Lim
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Article
| Open AccessExtended stop codon context predicts nonsense codon readthrough efficiency in human cells
Stop codon readthrough, the ribosomal bypass of mRNA nonsense codons, has therapeutic potential for diseases caused by nonsense mutations. Here, the authors used machine learning to define readthrough-conducive mRNA sequences and predict specific CFTR alleles likely amenable to readthrough therapy.
- Kotchaphorn Mangkalaphiban
- , Lianwu Fu
- & Allan Jacobson
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Article
| Open AccessA universal molecular control for DNA, mRNA and protein expression
Multi-omics analyses powerfully combine gene expression and translation, however no available controls can be used across these techniques. Here the authors develop pREF, a universal control construct designed for use in DNA, RNA and protein analyses.
- Helen M. Gunter
- , Scott E. Youlten
- & Tim R. Mercer
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Article
| Open AccessOne-Tip enables comprehensive proteome coverage in minimal cells and single zygotes
Traditional proteomics methods are complex and resource-intensive. Here, the authors develop One-Tip, a highly simplified approach that enables efficient, sensitive, and comprehensive analysis across various sample types, from blood plasma to single cells.
- Zilu Ye
- , Pierre Sabatier
- & Jesper V. Olsen
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Article
| Open AccessDissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level
The detailed process of membrane fusion mediated by dynamin-like GTPase atlastin (ATL) remains unclear. Here, authors reveal the conformational dynamics of ATL coupled with GTP hydrolysis cycle at the single molecule level.
- Lijun Shi
- , Chenguang Yang
- & Xin Bian
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Article
| Open AccessEpigenetic modulators link mitochondrial redox homeostasis to cardiac function in a sex-dependent manner
Efforts to treat heart failure with antioxidants have failed. Here, authors reveal a robust sex-dependent endogenous defense against oxidative damage and demonstrate antioxidative treatment’s efficacy solely in subjects with inadequate redox capacity.
- Zaher ElBeck
- , Mohammad Bakhtiar Hossain
- & Christer Betsholtz
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Article
| Open AccessOncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory
Metastasis arises from disseminated tumour cells (DTCs) while the underlying mechanism of DTCs plasticity remains underexplored. Here, the authors show that spatially organized oncogenic enhancers on chromatin sustain the establishment of retinoic acid (RA)-stimulated transcriptional memory through activation of SOX9, supporting the escape of quiescent DTCs from NK-mediated immune surveillance.
- Daniela Michelatti
- , Sven Beyes
- & Alessio Zippo
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Article
| Open AccessTwo DOT1 enzymes cooperatively mediate efficient ubiquitin-independent histone H3 lysine 76 tri-methylation in kinetoplastids
Trypanosoma brucei DOT1A and DOT1B methylate H3K76 without H2B-ubiquitin. Based on structural and enzymatic data, Frisbie et al. reveal a mechanism of how these enzymes cooperatively and efficiently tri-methylate H3K76 in a ubiquitin-independent way.
- Victoria S. Frisbie
- , Hideharu Hashimoto
- & Erik W. Debler
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Article
| Open AccessVCF1 is a p97/VCP cofactor promoting recognition of ubiquitylated p97-UFD1-NPL4 substrates
p97/VCP, a nexus of the ubiquitin system, recognizes and unfolds ubiquitylated substrates via multiple cofactors. Here, the authors identify VCF1, a nuclear cofactor promoting p97 recruitment to, and proteasomal degradation of, ubiquitylated targets.
- Ann Schirin Mirsanaye
- , Saskia Hoffmann
- & Niels Mailand
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Article
| Open AccessThe SecM arrest peptide traps a pre-peptide bond formation state of the ribosome
Stalling of ribosomes by the nascent polypeptide chain is widely used to regulate gene expression. Here, Gersteuer et al determine cryo-EM structures of SecM-stalled ribosomes revealing the mechanism by which the SecM peptide arrests translation.
- Felix Gersteuer
- , Martino Morici
- & Daniel N. Wilson
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