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EMBO Journal

Cosmas D Arnold, Filip Nemčko, Ashley R Woodfin, Sebastian Wienerroither, Anna Vlasova, Alexander Schleiffer, Michaela Pagani, Martina Rath, Alexander Stark
Even though transcription factors (TFs) are central players of gene regulation and have been extensively studied, their regulatory trans -activation domains (tADs) often remain unknown and a systematic functional characterization of tADs is lacking. Here, we present a novel high-throughput approach tAD-seq to functionally test thousands of candidate tADs from different TFs in parallel. The tADs we identify by pooled screening validate in individual luciferase assays, whereas neutral regions do not. Interestingly, the tADs are found at arbitrary positions within the TF sequences and can contain amino acid (e...
July 13, 2018: EMBO Journal
Shiho Ogawa, Sayuri Kido, Tetsuya Handa, Hidesato Ogawa, Haruhiko Asakawa, Tatsuro S Takahashi, Takuro Nakagawa, Yasushi Hiraoka, Hisao Masukata
DNA replication initiates at many discrete loci on eukaryotic chromosomes, and individual replication origins are regulated under a spatiotemporal program. However, the underlying mechanisms of this regulation remain largely unknown. In the fission yeast Schizosaccharomyces pombe , the telomere-binding protein Taz1, ortholog of human TRF1/TRF2, regulates a subset of late replication origins by binding to the telomere-like sequence near the origins. Here, we showed using a lacO /LacI-GFP system that Taz1-dependent late origins were predominantly localized at the nuclear periphery throughout interphase, and were localized adjacent to the telomeres in the G1/S phase...
July 11, 2018: EMBO Journal
Katja Rust, Manu D Tiwari, Vivek Kumar Mishra, Ferdi Grawe, Andreas Wodarz
Stem cells establish cortical polarity and divide asymmetrically to simultaneously maintain themselves and generate differentiating offspring cells. Several chromatin modifiers have been identified as stemness factors in mammalian pluripotent stem cells, but whether these factors control stem cell polarity and asymmetric division has not been investigated so far. We addressed this question in Drosophila neural stem cells called neuroblasts. We identified the Tip60 chromatin remodeling complex and its interaction partner Myc as regulators of genes required for neuroblast maintenance...
July 11, 2018: EMBO Journal
Jingjin Ding, Feng Shao
No abstract text is available yet for this article.
July 11, 2018: EMBO Journal
David Bending, Alina Paduraru, Catherine B Ducker, Paz Prieto Martín, Tessa Crompton, Masahiro Ono
Regulatory T cells (Treg) are negative regulators of the immune response; however, it is poorly understood whether and how Foxp3 transcription is induced and regulated in the periphery during T-cell responses. Using Foxp3 -Timer of cell kinetics and activity (Tocky) mice, which report real-time Foxp3 expression , we show that the flux of new Foxp3 expressors and the rate of Foxp3 transcription are increased during inflammation. These persistent dynamics of Foxp3 transcription determine the effector Treg programme and are dependent on a Foxp3 autoregulatory transcriptional circuit...
July 10, 2018: EMBO Journal
Lindsey A Allan, Agnieszka Skowyra, Katie I Rogers, Désirée Zeller, Paul R Clarke
The initiation of apoptosis in response to the disruption of mitosis provides surveillance against chromosome instability. Here, we show that proteolytic destruction of the key regulator Mcl-1 during an extended mitosis requires the anaphase-promoting complex or cyclosome (APC/C) and is independent of another ubiquitin E3 ligase, SCFFbw7 Using live-cell imaging, we show that the loss of Mcl-1 during mitosis is dependent on a D box motif found in other APC/C substrates, while an isoleucine-arginine (IR) C-terminal tail regulates the manner in which Mcl-1 engages with the APC/C, converting Mcl-1 from a Cdc20-dependent and checkpoint-controlled substrate to one that is degraded independently of checkpoint strength...
July 9, 2018: EMBO Journal
Jon V Busto, Annegret Elting, Daniel Haase, Felix Spira, Julian Kuhlman, Marco Schäfer-Herte, Roland Wedlich-Söldner
Biological membranes organize their proteins and lipids into nano- and microscale patterns. In the yeast plasma membrane (PM), constituents segregate into a large number of distinct domains. However, whether and how this intricate patchwork contributes to biological functions at the PM is still poorly understood. Here, we reveal an elaborate interplay between PM compartmentalization, physiological function, and endocytic turnover. Using the methionine permease Mup1 as model system, we demonstrate that this transporter segregates into PM clusters...
July 5, 2018: EMBO Journal
Stefan F Lichtenthaler, Marius K Lemberg, Regina Fluhrer
Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post-translational modification that controls levels and function of hundreds of membrane proteins. The contributing proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the "a disintegrin and metalloprotease" (ADAM) and "beta-site APP cleaving enzyme" (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions...
July 5, 2018: EMBO Journal
Thomas Bonacci, Aussie Suzuki, Gavin D Grant, Natalie Stanley, Jeanette G Cook, Nicholas G Brown, Michael J Emanuele
The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and key regulator of cell cycle progression. Since APC/C promotes the degradation of mitotic cyclins, it controls cell cycle-dependent oscillations in cyclin-dependent kinase (CDK) activity. Both CDKs and APC/C control a large number of substrates and are regulated by analogous mechanisms, including cofactor-dependent activation. However, whereas substrate dephosphorylation is known to counteract CDK, it remains largely unknown whether deubiquitinating enzymes (DUBs) antagonize APC/C substrate ubiquitination during mitosis...
July 4, 2018: EMBO Journal
Hyunju Cho, Shu-Ou Shan
Membrane proteins are aggregation-prone in aqueous environments, and their biogenesis poses acute challenges to cellular protein homeostasis. How the chaperone network effectively protects integral membrane proteins during their post-translational targeting is not well understood. Here, biochemical reconstitutions showed that the yeast cytosolic Hsp70 is responsible for capturing newly synthesized tail-anchored membrane proteins (TAs) in the soluble form. Moreover, direct interaction of Hsp70 with the cochaperone Sgt2 initiates a sequential series of TA relays to the dedicated TA targeting factor Get3...
July 4, 2018: EMBO Journal
Alessandra Sclip, Claudio Acuna, Fujun Luo, Thomas C Südhof
The active zone of presynaptic nerve terminals organizes the neurotransmitter release machinery, thereby enabling fast Ca2+ -triggered synaptic vesicle exocytosis. BK-channels are Ca2+ -activated large-conductance K+ -channels that require close proximity to Ca2+ -channels for activation and control Ca2+ -triggered neurotransmitter release by accelerating membrane repolarization during action potential firing. How BK-channels are recruited to presynaptic Ca2+ -channels, however, is unknown. Here, we show that RBPs (for RIM-binding proteins), which are evolutionarily conserved active zone proteins containing SH3- and FN3-domains, directly bind to BK-channels...
July 2, 2018: EMBO Journal
Mary McMahon, Davide Ruggero
No abstract text is available yet for this article.
July 2, 2018: EMBO Journal
Maria Benitez-Guijarro, Cesar Lopez-Ruiz, Žygimantė Tarnauskaitė, Olga Murina, Mahwish Mian Mohammad, Thomas C Williams, Adeline Fluteau, Laura Sanchez, Raquel Vilar-Astasio, Marta Garcia-Canadas, David Cano, Marie-Jeanne Hc Kempen, Antonio Sanchez-Pozo, Sara R Heras, Andrew P Jackson, Martin Am Reijns, Jose L Garcia-Perez
Long INterspersed Element class 1 (LINE-1) elements are a type of abundant retrotransposons active in mammalian genomes. An average human genome contains ~100 retrotransposition-competent LINE-1s, whose activity is influenced by the combined action of cellular repressors and activators. TREX1, SAMHD1 and ADAR1 are known LINE-1 repressors and when mutated cause the autoinflammatory disorder Aicardi-Goutières syndrome (AGS). Mutations in RNase H2 are the most common cause of AGS, and its activity was proposed to similarly control LINE-1 retrotransposition...
June 29, 2018: EMBO Journal
Eva Parisi, Galal Yahya, Alba Flores, Martí Aldea
Cells sense myriad signals during G1, and a rapid response to prevent cell cycle entry is of crucial importance for proper development and adaptation. Cln3, the most upstream G1 cyclin in budding yeast, is an extremely short-lived protein subject to ubiquitination and proteasomal degradation. On the other hand, nuclear accumulation of Cln3 depends on chaperones that are also important for its degradation. However, how these processes are intertwined to control G1-cyclin fate is not well understood. Here, we show that Cln3 undergoes a challenging ubiquitination step required for both degradation and full activation...
June 27, 2018: EMBO Journal
Sven Truckenbrodt, Abhiyan Viplav, Sebastian Jähne, Angela Vogts, Annette Denker, Hanna Wildhagen, Eugenio F Fornasiero, Silvio O Rizzoli
Aged proteins can become hazardous to cellular function, by accumulating molecular damage. This implies that cells should preferentially rely on newly produced ones. We tested this hypothesis in cultured hippocampal neurons, focusing on synaptic transmission. We found that newly synthesized vesicle proteins were incorporated in the actively recycling pool of vesicles responsible for all neurotransmitter release during physiological activity. We observed this for the calcium sensor Synaptotagmin 1, for the neurotransmitter transporter VGAT, and for the fusion protein VAMP2 (Synaptobrevin 2)...
June 27, 2018: EMBO Journal
Emily N Truckenbrod, Stephen C Jameson
No abstract text is available yet for this article.
June 26, 2018: EMBO Journal
François-Xavier Blaudin de Thé, Hocine Rekaik, Eugenie Peze-Heidsieck, Olivia Massiani-Beaudoin, Rajiv L Joshi, Julia Fuchs, Alain Prochiantz
LINE-1 mobile genetic elements have shaped the mammalian genome during evolution. A minority of them have escaped fossilization which, when activated, can threaten genome integrity. We report that LINE-1 are expressed in substantia nigra ventral midbrain dopaminergic neurons, a class of neurons that degenerate in Parkinson's disease. In Engrailed-1 heterozygotes, these neurons show a progressive degeneration that starts at 6 weeks of age, coinciding with an increase in LINE-1 expression. Similarly, DNA damage and cell death, induced by an acute oxidative stress applied to embryonic midbrain neurons in culture or to adult midbrain dopaminergic neurons in vivo , are accompanied by enhanced LINE-1 expression...
June 25, 2018: EMBO Journal
Percy Tumbale, Matthew J Schellenberg, Geoffrey A Mueller, Emma Fairweather, Mandy Watson, Jessica N Little, Juno Krahn, Ian Waddell, Robert E London, R Scott Williams
The failure of DNA ligases to complete their catalytic reactions generates cytotoxic adenylated DNA strand breaks. The APTX RNA-DNA deadenylase protects genome integrity and corrects abortive DNA ligation arising during ribonucleotide excision repair and base excision DNA repair, and APTX human mutations cause the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1). How APTX senses cognate DNA nicks and is inactivated in AOA1 remains incompletely defined. Here, we report X-ray structures of APTX engaging nicked RNA-DNA substrates that provide direct evidence for a wedge-pivot-cut strategy for 5'-AMP resolution shared with the alternate 5'-AMP processing enzymes POLβ and FEN1...
June 22, 2018: EMBO Journal
Miroslav P Ivanov, Rene Ladurner, Ina Poser, Rebecca Beveridge, Evelyn Rampler, Otto Hudecz, Maria Novatchkova, Jean-Karim Hériché, Gordana Wutz, Petra van der Lelij, Emanuel Kreidl, James Ra Hutchins, Heinz Axelsson-Ekker, Jan Ellenberg, Anthony A Hyman, Karl Mechtler, Jan-Michael Peters
Chromosome segregation depends on sister chromatid cohesion which is established by cohesin during DNA replication. Cohesive cohesin complexes become acetylated to prevent their precocious release by WAPL before cells have reached mitosis. To obtain insight into how DNA replication, cohesion establishment and cohesin acetylation are coordinated, we analysed the interaction partners of 55 human proteins implicated in these processes by mass spectrometry. This proteomic screen revealed that on chromatin the cohesin acetyltransferase ESCO2 associates with the MCM2-7 subcomplex of the replicative Cdc45-MCM-GINS helicase...
June 21, 2018: EMBO Journal
Amandine Viau, Frank Bienaimé, Kamile Lukas, Abhijeet P Todkar, Manuel Knoll, Toma A Yakulov, Alexis Hofherr, Oliver Kretz, Martin Helmstädter, Wilfried Reichardt, Simone Braeg, Tom Aschman, Annette Merkle, Dietmar Pfeifer, Verónica I Dumit, Marie-Claire Gubler, Roland Nitschke, Tobias B Huber, Fabiola Terzi, Jörn Dengjel, Florian Grahammer, Michael Köttgen, Hauke Busch, Melanie Boerries, Gerd Walz, Antigoni Triantafyllopoulou, E Wolfgang Kuehn
Polycystic kidney disease (PKD) and other renal ciliopathies are characterized by cysts, inflammation, and fibrosis. Cilia function as signaling centers, but a molecular link to inflammation in the kidney has not been established. Here, we show that cilia in renal epithelia activate chemokine signaling to recruit inflammatory cells. We identify a complex of the ciliary kinase LKB1 and several ciliopathy-related proteins including NPHP1 and PKD1. At homeostasis, this ciliary module suppresses expression of the chemokine CCL2 in tubular epithelial cells...
June 19, 2018: EMBO Journal
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