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| Open AccessSWI/SNF catalytic subunits’ switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells
The mechanism of resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations is unknown. Here, the authors demonstrate that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells.
- Shuai Wu
- , Nail Fatkhutdinov
- & Rugang Zhang
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Article
| Open AccessEnhanced validation of antibodies for research applications
Five validation pillars have been proposed to verify the specificity of research antibodies. Here the authors screen 6,000 antibodies from the Human Protein Atlas with these methods to provide an antibody validation resource for providers and users.
- Fredrik Edfors
- , Andreas Hober
- & Mathias Uhlen
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Article
| Open AccessFormation of the β-barrel assembly machinery complex in lipid bilayers as seen by solid-state NMR
The β-barrel assembly machinery (BAM) catalyzes β-barrel protein insertion into the outer membrane of E.coli. Here authors employ high-sensitivity solid-state NMR to reveal how the lipid environment and formation of the BamA-BamCDE complex affect BamA structure and dynamics with regards to the lateral gate and the β-barrel associated domains.
- Cecilia Pinto
- , Deni Mance
- & Marc Baldus
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Article
| Open AccessATR/Chk1 signaling induces autophagy through sumoylated RhoB-mediated lysosomal translocation of TSC2 after DNA damage
DNA damage can lead to autophagy. Here the authors reveal a molecular mechanism for ATR/Chk1 signaling-induced autophagy in response to DNA damage, through an ATR/Chk1/RhoB-mediated lysosomal recruitment of TSC complex and subsequent mTORC1 inhibition.
- Mingdong Liu
- , Taoling Zeng
- & Hong-Rui Wang
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Article
| Open AccessGenetic and mechanistic basis for APOBEC3H alternative splicing, retrovirus restriction, and counteraction by HIV-1 protease
Human APOBEC3H has several haplotypes and splice variants with distinct anti-HIV-1 activities, but the genetics underlying the expression of these variants are unclear. Here, the authors identify an intronic deletion in A3H haplotype II resulting in production of the most active splice variant, which is counteracted by HIV-1 protease.
- Diako Ebrahimi
- , Christopher M. Richards
- & Reuben S. Harris
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Article
| Open AccessIntestinal microbiome adjusts the innate immune setpoint during colonization through negative regulation of MyD88
It remains unclear how microbial sensing during early-life colonization results in immune homeostasis rather than acute inflammation. Here the authors show that zebrafish larvae colonization suppresses intestinal MyD88, accounting for a considerable proportion of microbiota-induced alterations in immune setpoint.
- Bjørn E. V. Koch
- , Shuxin Yang
- & Herman P. Spaink
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Article
| Open AccessSuppressor mutations in Rpf2–Rrs1 or Rpl5 bypass the Cgr1 function for pre-ribosomal 5S RNP-rotation
During biogenesis of the eukaryotic 60S ribosome, a large rotational movement of the 5S RNP is required to achieve its mature position. By analyzing extragenic suppressors of crg1—a key factor required for rotation—the authors provide mechanistic insight into a key step of ribosome biogenesis.
- Matthias Thoms
- , Valentin Mitterer
- & Ed Hurt
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Article
| Open AccessDNA damage sensitivity of SWI/SNF-deficient cells depends on TFIIH subunit p62/GTF2H1
SWI/SNF genes are commonly found to be mutated in different cancers. Here the authors report that the remodelers BRM and BRG1 are necessary for efficient nucleotide excision repair by promoting the expression of TFIIH subunit GTF2H1.
- Cristina Ribeiro-Silva
- , Özge Z. Aydin
- & Wim Vermeulen
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Article
| Open AccessCell cycle-resolved chromatin proteomics reveals the extent of mitotic preservation of the genomic regulatory landscape
Mitosis poses a challenge for transcriptional programs, as it is thought that several proteins lose binding on condensed chromosomes. Here, the authors analyze the chromatin-bound proteome through the cell cycle, revealing retention of most transcription factors and preservation of the regulatory landscape.
- Paul Adrian Ginno
- , Lukas Burger
- & Dirk Schübeler
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Article
| Open AccessAnalysis of chromatin accessibility uncovers TEAD1 as a regulator of migration in human glioblastoma
The intrinsic drivers of glioblastoma (GBM) migration are still poorly understood. Here the authors purify GBM stem cells (GSCs) from patients and profile chromatin accessibility in these cells, identifying TEAD1 as a regulator of migration in human glioblastoma.
- Jessica Tome-Garcia
- , Parsa Erfani
- & Nadejda M. Tsankova
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Article
| Open AccessRegulatory control of DNA end resection by Sae2 phosphorylation
It has previously been established that DNA end resection in yeast and in humans is under CDK control. Here the authors explain how phosphorylation regulates the capacity of Sae2 — the yeast orthologue of human CtIP — to promote DNA end resection.
- Elda Cannavo
- , Dominic Johnson
- & Petr Cejka
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Article
| Open AccessMethylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
Around 10% of high-grade serous ovarian carcinomas (HGSOC) harbor BRCA1 promoter methylation, but it is uncertain how it predicts response to PARP inhibition. Here, the authors show that homozygous BRCA1 methylation predicts response to rucaparib while heterozygous methylation of BRCA1 predicts resistance in HGSOC.
- Olga Kondrashova
- , Monique Topp
- & Clare L. Scott
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Article
| Open AccessUSP24 induces IL-6 in tumor-associated microenvironment by stabilizing p300 and β-TrCP and promotes cancer malignancy
USP24 has previously been reported to be involved in cancer progression. Here, the authors demonstrate that USP24 stabilizes p300 and β-TrCP to increase the levels of NF-κB and histone-3 acetylation, and decrease DNMT1 and IκB levels which promotes IL-6 expression in M2 macrophages and lung cancer cells.
- Yi-Chang Wang
- , Yu-Syuan Wu
- & Jan-Jong Hung
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Article
| Open AccessSystems biology approach reveals a link between mTORC1 and G2/M DNA damage checkpoint recovery
DNA damage induces checkpoints to ensure that damage is not transferred to the next generation, but the molecular pathways responsible for checkpoint recovery are not clear. Here the authors show that the nutrient sensor mTORC1 is a determinant for G2/M checkpoint recovery through regulation of cyclin B1 and PLK1 expression.
- Hui-Ju Hsieh
- , Wei Zhang
- & Guang Peng
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Article
| Open AccessIntracellular nucleosomes constrain a DNA linking number difference of −1.26 that reconciles the Lk paradox
There had been an enduring discrepancy between theoretical and observed measurement of the DNA linking number (∆Lk) constrained by nucleosomes. Here the authors provide measurements of the ∆Lk constrained by individual nucleosomes in native chromatin that reconcile this discrepancy.
- Joana Segura
- , Ricky S. Joshi
- & Joaquim Roca
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Article
| Open AccessRegulatory mechanisms of incomplete huntingtin mRNA splicing
Incomplete splicing of HTT results in the production of the highly pathogenic exon 1 HTT protein. Here the authors identify the necessary intronic regions and the underlying mechanisms that contribute to this process.
- Andreas Neueder
- , Anaelle A. Dumas
- & Gillian P. Bates
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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 AccessNuclear lamina dysfunction triggers a germline stem cell checkpoint
Otefin is a nuclear lamina protein required for survival of Drosophila germ stem cells. Here the authors show that nuclear lamina dysfunction resulting from loss of Otefin activates a DNA damage-independent germ stem cell-specific checkpoint, mediated by the ATR and Chk2 kinases, which ensures that healthy gametes are passed on to the next generation.
- Lacy J. Barton
- , Tingting Duan
- & Pamela K. Geyer
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Article
| Open AccessUBL3 modification influences protein sorting to small extracellular vesicles
Exosomes mediate cell-to-cell communication by transporting proteins, mRNAs, and miRNAs but the mechanisms of protein sorting to exosomes are poorly understood. Here, the authors uncover that ubiquitin-like 3 (UBL3) regulates protein sorting to exosomes by acting as a posttranslational modification.
- Hiroshi Ageta
- , Natsumi Ageta-Ishihara
- & Kunihiro Tsuchida
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Article
| Open AccessPersistent repair intermediates induce senescence
Cells with damaged DNA can permanently exit the cell cycle during the G2 phase or recover spontaneously entering mitosis. Here the authors reveal that the decision to exit from the cell cycle in G2 is dependent on the presence of repair intermediates associated with homologous recombination.
- F. M. Feringa
- , J. A. Raaijmakers
- & R. H. Medema
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Article
| Open AccessAn OB-fold complex controls the repair pathways for DNA double-strand breaks
How repair pathway selection occurs is still a matter of debate and many factors have been associated to this function. Here the authors provide insight into the role of FAM35A and C20ORF196, two REV7-interacting proteins, which are recruited at double-strand breaks to promote non-homologous end joining repair.
- Shengxian Gao
- , Sumin Feng
- & Dongyi Xu
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Article
| Open AccessLnk/Sh2b3 deficiency restores hematopoietic stem cell function and genome integrity in Fancd2 deficient Fanconi anemia
Loss of Fancd2 leads to replication stress intolerance and Fanconi Anemia, where haematopoietic stem cell (HSC) function is compromised. Here, the authors show that Lnk/Sh2b3 loss restores HSC proliferation and survival in Fancd2 knockout mice and ameliorates replication stress in a cytokine/JAK2 signaling dependent manner.
- Joanna Balcerek
- , Jing Jiang
- & Wei Tong
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Article
| Open AccessLUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L
TNF mediated inflammation is critical in autoimmune mediated pathology, however many patients are refractory to current anti-TNF therapeutics. Here the authors show induction of several death ligands, in addition to TNF is sufficient to cause fatal dermatitis in a LUBAC deficient murine model of disease.
- Lucia Taraborrelli
- , Nieves Peltzer
- & Henning Walczak
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Article
| Open AccessLoss of PRC1 induces higher-order opening of Hox loci independently of transcription during Drosophila embryogenesis
Loss of Polycomb repressive complex 1 (PRC1) proteins usually results in both chromatin unfolding and ectopic transcription. Here, the authors analyze the temporal function of two PRC1 proteins during Drosophila embryogenesis and provide evidence that PRC1 maintains gene silencing by folding chromatin domains.
- Thierry Cheutin
- & Giacomo Cavalli
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Article
| Open AccessSpatiotemporal dynamics of homologous recombination repair at single collapsed replication forks
How factors involved in homologous recombination interact and function is a matter of interest. Here the authors use super-resolution imaging to describe the spatiotemporal dynamics of proteins associated with homologous recombination DNA repair in response to replication stress.
- Donna R. Whelan
- , Wei Ting C. Lee
- & Eli Rothenberg
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Article
| Open AccessMapping of histone-binding sites in histone replacement-completed spermatozoa
While a majority of histones are replaced by protamines during spermatogenesis, a small amount is retained in mammalian spermatozoa. Here the authors develop a method to purify histones from replacement-completed sperm (HRCS), completely solubilize histones from cross-linked HRCS without MNase digestion, and map histone-binding sites in these cells.
- Keisuke Yoshida
- , Masafumi Muratani
- & Shunsuke Ishii
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Article
| Open AccessTargeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination
Targeting the glycolytic PFKFB3 enzyme is being studied as a therapeutic strategy against cancer. Here the authors identify PFKFB3 as being involved in homologous recombination (HR) repair of DNA double strand breaks (DSBs) and present a PFKFB3 inhibitor.
- Nina M. S. Gustafsson
- , Katarina Färnegårdh
- & Thomas Helleday
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Article
| Open AccessPAXX and its paralogs synergistically direct DNA polymerase λ activity in DNA repair
PAXX functions as part of the nonhomologous end-joining pathway to repair double-strand DNA breaks. Here the authors show PAXX and its paralogs interact with polymerase lambda to promote joining of incompatible ends.
- Andrew Craxton
- , Deeksha Munnur
- & Michal Malewicz
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Article
| Open AccessA conformational sensor based on genetic code expansion reveals an autocatalytic component in EGFR activation
Upon ligand binding epidermal growth factor receptor (EGFR) dimerizes and activates its intrinsic kinase to auto-phosphorylate EGFR. Here, the authors engineer and image a FRET-based conformational EGFR indicator which reveals that activation loop phosphorylation induces a catalytically active conformation in EGFR monomers.
- Martin Baumdick
- , Márton Gelléri
- & Philippe I. H. Bastiaens
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Article
| Open AccessHierarchical and stage-specific regulation of murine cardiomyocyte maturation by serum response factor
The processes regulating cardiomyocyte (CM) maturation are unclear. Here, the authors show that serum response factor regulates CM maturation only in neonatal CMs through stage-specific chromatin occupancy that affects cell size, sarcomere and transverse-tubule organization, and mitochondria
- Yuxuan Guo
- , Blake D. Jardin
- & William T. Pu
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Article
| Open AccessA tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions
Self-interacting chromatin domains encompass genes and their cis-regulatory elements. Here the authors use high-resolution chromosome conformation capture and super-resolution imaging to study a 70 kb domain that includes the mouse α-globin regulatory locus and find that a tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions.
- Jill M. Brown
- , Nigel A. Roberts
- & Veronica J. Buckle
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Article
| Open AccessRobust single-cell DNA methylome profiling with snmC-seq2
Single-cell DNA methylome profiling allows the study of epigenomic heterogeneity in tissues but has been impeded by library quality. Here the authors demonstrate snmC-seq2 which improves mapping, throughput and library complexity.
- Chongyuan Luo
- , Angeline Rivkin
- & Joseph R. Ecker
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Article
| Open AccessFemale mice lacking Ftx lncRNA exhibit impaired X-chromosome inactivation and a microphthalmia-like phenotype
Although Ftx lncRNA has been linked to X-chromosome inactivation, its physiological roles in vivo remain unclear. Here the authors show that deletion of mouse Ftx causes eye abnormalities similar to human microphthalmia in a subset of female mice but rarely in males and provide evidence that Ftx plays a role in gene silencing on the inactive X chromosome.
- Yusuke Hosoi
- , Miki Soma
- & Shin Kobayashi
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Article
| Open AccessRoquin targets mRNAs in a 3′-UTR-specific manner by different modes of regulation
Roquin targets are known to contain two types of sequence-structure motifs, the constitutive and the alternative decay elements (CDE and ADE). Here, the authors describe a linear Roquin binding element (LBE) also involved in target recognition, and show that Roquin binding affects the translation of a subset of targeted mRNAs.
- Katharina Essig
- , Nina Kronbeck
- & Vigo Heissmeyer
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Article
| Open AccessA variant NuRD complex containing PWWP2A/B excludes MBD2/3 to regulate transcription at active genes
Transcription regulation requires recruitment of different epigenetic regulators to the chromatin. Here the authors provide evidence that an H3K36me3 reader PWWP2A forms a variant NuRD complex and plays a role in regulating transcription and histone acetylation dynamics.
- Tianyi Zhang
- , Guifeng Wei
- & Neil Brockdorff
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Article
| Open AccessThe ZZ-type zinc finger of ZZZ3 modulates the ATAC complex-mediated histone acetylation and gene activation
Histones are recognized by epigenetic readers, which play essential roles in regulation of chromatin and transcription. Here the authors provide evidence that the ZZ-type zinc finger domain of ZZZ3 functions as a reader of histone H3, which is required for the ATAC complex-mediated maintenance of histone acetylation and gene activation.
- Wenyi Mi
- , Yi Zhang
- & Xiaobing Shi
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Article
| Open AccessChromatin swelling drives neutrophil extracellular trap release
Neutrophilic granulocytes release their own DNA (NETosis) as neutrophil extracellular traps to capture pathogens. Here, the authors use time-resolved fluorescence and atomic force microscopy and reveal that NETosis is highly organized into three distinct phases with a clear point of no return defined by chromatin status.
- Elsa Neubert
- , Daniel Meyer
- & Sebastian Kruss
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Article
| Open AccessCharacterization and targeting of malignant stem cells in patients with advanced myelodysplastic syndromes
Myelodysplastic syndrome (MDS) arises from mutations in hematopoietic stem cells (HSCs). Here, the authors demonstrate that HSCs in higher-risk MDS express the surface marker CD123 and are characterized by activation of protein synthesis machinery and increased oxidative phosphorylation.
- Brett M. Stevens
- , Nabilah Khan
- & Craig T. Jordan
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Article
| Open AccessHistone H4K20 methylation mediated chromatin compaction threshold ensures genome integrity by limiting DNA replication licensing
Cell cycle and replication need to be tightly regulated to ensure genome stability in mammalian cells. Here the authors provide a link between chromatin structure and DNA replication regulation by showing that chromatin compaction limits replication licensing thereby promoting genome integrity.
- Muhammad Shoaib
- , David Walter
- & Claus S. Sørensen
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Article
| Open AccessThe Swr1 chromatin-remodeling complex prevents genome instability induced by replication fork progression defects
SWR-C and its substrate the histone variant Htz1 are considered important for genome maintenance. Here the authors reveal that SWR-C/Htz1 plays a critical role during replication stress caused by absence of the replication fork progression proteins Mrc1/Tof1/Csm3.
- Anjana Srivatsan
- , Bin-Zhong Li
- & Richard D. Kolodner
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Article
| Open AccessMutant FUS causes DNA ligation defects to inhibit oxidative damage repair in Amyotrophic Lateral Sclerosis
Impairment of DNA repair has been associated with neurodegeneration. Here the authors investigate the mechanisms of defects in repair caused by mutations in the RNA/DNA binding protein FUS in amyotrophic lateral sclerosis and elucidate its role in the DNA ligation during DNA single-strand break repair of oxidative breaks.
- Haibo Wang
- , Wenting Guo
- & Muralidhar L. Hegde
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Article
| Open AccessDifferent patterns of clonal evolution among different sarcoma subtypes followed for up to 25 years
Hofvander and colleagues compare the patterns of clonal evolution in different pathogenetic subgroups of sarcoma. They show that sarcomas driven by gene fusion or amplification display few additional changes over time, whereas sarcomas with complex karyotypes show a gradual increase of nucleotide- and chromosome-level mutations.
- Jakob Hofvander
- , Björn Viklund
- & Fredrik Mertens
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Article
| Open AccessER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes
HRD1 is an E3 ligase known to play a role in targeting degradation of misfolded proteins in the ER. Here the authors show that HRD1 interacts with metabolic enzymes and its liver specific deficiency results in lower body weight, blood glucose and plasma lipids during high fat diet in mice.
- Juncheng Wei
- , Yanzhi Yuan
- & Deyu Fang
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Article
| Open AccessDynamics of cellular states of fibro-adipogenic progenitors during myogenesis and muscular dystrophy
Fibro-adipogenic progenitors (FAPs) resident in skeletal muscle are involved in both regeneration and maladaptive processes. Here, the authors identify subpopulations of FAPs with biological activities implicated in physiological muscle repair that are altered in pathological conditions such as muscular dystrophies.
- Barbora Malecova
- , Sole Gatto
- & Pier Lorenzo Puri
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Article
| Open AccessHepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology
The RNA-induced silencing complex (RISC) represses gene expression via micro-RNA guided mRNA silencing. Here, the authors show that RISC component Argonaute 2 in the liver regulates energy metabolism by inducing microRNAs that cause metabolic disruption and by suppressing protein translation linked to AMPK activation.
- Cai Zhang
- , Joonbae Seo
- & Takahisa Nakamura
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Article
| Open AccessStaufen1 links RNA stress granules and autophagy in a model of neurodegeneration
Spinocerebellar ataxia type 2 (SCA2) is caused by polyglutamine repeats in the ATXN2 protein. Here the authors demonstrate that Staufen1, known to be an RNA-binding protein, interacts with ATXN2 and contributes to pathology in a mouse model of SCA2.
- Sharan Paul
- , Warunee Dansithong
- & Stefan M. Pulst
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Article
| Open AccessInterrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability
RAS isoforms are frequently mutated in cancer but their inhibition remains challenging. By comparing the protein interactomes of the highly similar isoforms HRAS, NRAS and KRAS, the authors here identify PIP5K1A as a KRAS-specific interactor and a target to inhibit KRAS-driven cell growth.
- Hema Adhikari
- & Christopher M. Counter
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Article
| Open AccessMapping molecular landmarks of human skeletal ontogeny and pluripotent stem cell-derived articular chondrocytes
Human development provides a roadmap for advancing pluripotent stem cell-based regenerative therapies. Here the authors mapped human skeletogenesis using RNA sequencing on 5 cell types from a single foetal stage as well as chondrocytes at 4 stages in vivo and 2 stages during in vitro differentiation.
- Gabriel B. Ferguson
- , Ben Van Handel
- & Denis Evseenko
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Article
| Open AccessJungle Express is a versatile repressor system for tight transcriptional control
Tightly regulated promoters with strong inducibility and scalability are highly desirable for biological applications. Here the authors describe ‘Jungle Express’, a EilR repressor-based broad host system activated by cationic dyes.
- Thomas L. Ruegg
- , Jose H. Pereira
- & Michael P. Thelen
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