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https://www.readbyqxmd.com/read/29033132/assembly-and-function-of-heterotypic-ubiquitin-chains-in-cell-cycle-and-protein-quality-control
#1
Richard G Yau, Kerstin Doerner, Erick R Castellanos, Diane L Haakonsen, Achim Werner, Nan Wang, X William Yang, Nadia Martinez-Martin, Marissa L Matsumoto, Vishva M Dixit, Michael Rape
Posttranslational modification with ubiquitin chains controls cell fate in all eukaryotes. Depending on the connectivity between subunits, different ubiquitin chain types trigger distinct outputs, as seen with K48- and K63-linked conjugates that drive protein degradation or complex assembly, respectively. Recent biochemical analyses also suggested roles for mixed or branched ubiquitin chains, yet without a method to monitor endogenous conjugates, the physiological significance of heterotypic polymers remained poorly understood...
October 11, 2017: Cell
https://www.readbyqxmd.com/read/29033130/tumor-and-microenvironment-evolution-during-immunotherapy-with-nivolumab
#2
Nadeem Riaz, Jonathan J Havel, Vladimir Makarov, Alexis Desrichard, Walter J Urba, Jennifer S Sims, F Stephen Hodi, Salvador Martín-Algarra, Rajarsi Mandal, William H Sharfman, Shailender Bhatia, Wen-Jen Hwu, Thomas F Gajewski, Craig L Slingluff, Diego Chowell, Sviatoslav M Kendall, Han Chang, Rachna Shah, Fengshen Kuo, Luc G T Morris, John-William Sidhom, Jonathan P Schneck, Christine E Horak, Nils Weinhold, Timothy A Chan
The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy...
October 11, 2017: Cell
https://www.readbyqxmd.com/read/29033133/natively-unfolded-fg-repeats-stabilize-the-structure-of-the-nuclear-pore-complex
#3
Evgeny Onischenko, Jeffrey H Tang, Kasper R Andersen, Kevin E Knockenhauer, Pascal Vallotton, Carina P Derrer, Annemarie Kralt, Christopher F Mugler, Leon Y Chan, Thomas U Schwartz, Karsten Weis
Nuclear pore complexes (NPCs) are ∼100 MDa transport channels assembled from multiple copies of ∼30 nucleoporins (Nups). One-third of these Nups contain phenylalanine-glycine (FG)-rich repeats, forming a diffusion barrier, which is selectively permeable for nuclear transport receptors that interact with these repeats. Here, we identify an additional function of FG repeats in the structure and biogenesis of the yeast NPC. We demonstrate that GLFG-containing FG repeats directly bind to multiple scaffold Nups in vitro and act as NPC-targeting determinants in vivo...
October 7, 2017: Cell
https://www.readbyqxmd.com/read/29033131/oxysterol-restraint-of-cholesterol-synthesis-prevents-aim2-inflammasome-activation
#4
Eric V Dang, Jeffrey G McDonald, David W Russell, Jason G Cyster
Type I interferon restrains interleukin-1β (IL-1β)-driven inflammation in macrophages by upregulating cholesterol-25-hydroxylase (Ch25h) and repressing SREBP transcription factors. However, the molecular links between lipid metabolism and IL-1β production remain obscure. Here, we demonstrate that production of 25-hydroxycholesterol (25-HC) by macrophages is required to prevent inflammasome activation by the DNA sensor protein absent in melanoma 2 (AIM2). We find that in response to bacterial infection or lipopolysaccharide (LPS) stimulation, macrophages upregulate Ch25h to maintain repression of SREBP2 activation and cholesterol synthesis...
October 7, 2017: Cell
https://www.readbyqxmd.com/read/29033129/genome-nuclear-lamina-interactions-regulate-cardiac-stem-cell-lineage-restriction
#5
Andrey Poleshko, Parisha P Shah, Mudit Gupta, Apoorva Babu, Michael P Morley, Lauren J Manderfield, Jamie L Ifkovits, Damelys Calderon, Haig Aghajanian, Javier E Sierra-Pagán, Zheng Sun, Qiaohong Wang, Li Li, Nicole C Dubois, Edward E Morrisey, Mitchell A Lazar, Cheryl L Smith, Jonathan A Epstein, Rajan Jain
Progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. We demonstrate that a histone deacetylase (Hdac3) organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Specification of cardiomyocytes is associated with reorganization of peripheral heterochromatin, and independent of deacetylase activity, Hdac3 tethers peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina...
October 7, 2017: Cell
https://www.readbyqxmd.com/read/29033128/the-dna-inflammasome-in-human-myeloid-cells-is-initiated-by-a-sting-cell-death-program-upstream-of-nlrp3
#6
Moritz M Gaidt, Thomas S Ebert, Dhruv Chauhan, Katharina Ramshorn, Francesca Pinci, Sarah Zuber, Fionan O'Duill, Jonathan L Schmid-Burgk, Florian Hoss, Raymund Buhmann, Georg Wittmann, Eicke Latz, Marion Subklewe, Veit Hornung
Detection of cytosolic DNA constitutes a central event in the context of numerous infectious and sterile inflammatory conditions. Recent studies have uncovered a bipartite mode of cytosolic DNA recognition, in which the cGAS-STING axis triggers antiviral immunity, whereas AIM2 triggers inflammasome activation. Here, we show that AIM2 is dispensable for DNA-mediated inflammasome activation in human myeloid cells. Instead, detection of cytosolic DNA by the cGAS-STING axis induces a cell death program initiating potassium efflux upstream of NLRP3...
October 7, 2017: Cell
https://www.readbyqxmd.com/read/29033127/mechanism-of-transcription-anti-termination-in-human-mitochondria
#7
Hauke S Hillen, Andrey V Parshin, Karen Agaronyan, Yaroslav I Morozov, James J Graber, Aleksandar Chernev, Kathrin Schwinghammer, Henning Urlaub, Michael Anikin, Patrick Cramer, Dmitry Temiakov
In human mitochondria, transcription termination events at a G-quadruplex region near the replication origin are thought to drive replication of mtDNA by generation of an RNA primer. This process is suppressed by a key regulator of mtDNA-the transcription factor TEFM. We determined the structure of an anti-termination complex in which TEFM is bound to transcribing mtRNAP. The structure reveals interactions of the dimeric pseudonuclease core of TEFM with mobile structural elements in mtRNAP and the nucleic acid components of the elongation complex (EC)...
October 7, 2017: Cell
https://www.readbyqxmd.com/read/28988771/egfr-ligands-differentially-stabilize-receptor-dimers-to-specify-signaling-kinetics
#8
Daniel M Freed, Nicholas J Bessman, Anatoly Kiyatkin, Emanuel Salazar-Cavazos, Patrick O Byrne, Jason O Moore, Christopher C Valley, Kathryn M Ferguson, Daniel J Leahy, Diane S Lidke, Mark A Lemmon
Epidermal growth factor receptor (EGFR) regulates many crucial cellular programs, with seven different activating ligands shaping cell signaling in distinct ways. Using crystallography and other approaches, we show how the EGFR ligands epiregulin (EREG) and epigen (EPGN) stabilize different dimeric conformations of the EGFR extracellular region. As a consequence, EREG or EPGN induce less stable EGFR dimers than EGF-making them partial agonists of EGFR dimerization. Unexpectedly, this weakened dimerization elicits more sustained EGFR signaling than seen with EGF, provoking responses in breast cancer cells associated with differentiation rather than proliferation...
October 4, 2017: Cell
https://www.readbyqxmd.com/read/28988770/structural-basis-for-a-safety-belt-mechanism-that-anchors-condensin-to-chromosomes
#9
Marc Kschonsak, Fabian Merkel, Shveta Bisht, Jutta Metz, Vladimir Rybin, Markus Hassler, Christian H Haering
Condensin protein complexes coordinate the formation of mitotic chromosomes and thereby ensure the successful segregation of replicated genomes. Insights into how condensin complexes bind to chromosomes and alter their topology are essential for understanding the molecular principles behind the large-scale chromatin rearrangements that take place during cell divisions. Here, we identify a direct DNA-binding site in the eukaryotic condensin complex, which is formed by its Ycg1(Cnd3) HEAT-repeat and Brn1(Cnd2) kleisin subunits...
October 4, 2017: Cell
https://www.readbyqxmd.com/read/28988769/comprehensive-molecular-characterization-of-muscle-invasive-bladder-cancer
#10
A Gordon Robertson, Jaegil Kim, Hikmat Al-Ahmadie, Joaquim Bellmunt, Guangwu Guo, Andrew D Cherniack, Toshinori Hinoue, Peter W Laird, Katherine A Hoadley, Rehan Akbani, Mauro A A Castro, Ewan A Gibb, Rupa S Kanchi, Dmitry A Gordenin, Sachet A Shukla, Francisco Sanchez-Vega, Donna E Hansel, Bogdan A Czerniak, Victor E Reuter, Xiaoping Su, Benilton de Sa Carvalho, Vinicius S Chagas, Karen L Mungall, Sara Sadeghi, Chandra Sekhar Pedamallu, Yiling Lu, Leszek J Klimczak, Jiexin Zhang, Caleb Choo, Akinyemi I Ojesina, Susan Bullman, Kristen M Leraas, Tara M Lichtenberg, Catherine J Wu, Nicholaus Schultz, Gad Getz, Matthew Meyerson, Gordon B Mills, David J McConkey, John N Weinstein, David J Kwiatkowski, Seth P Lerner
We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology...
October 4, 2017: Cell
https://www.readbyqxmd.com/read/28988768/crosstalk-between-kcnk3-mediated-ion-current-and-adrenergic-signaling-regulates-adipose-thermogenesis-and-obesity
#11
Yi Chen, Xing Zeng, Xuan Huang, Sara Serag, Clifford J Woolf, Bruce M Spiegelman
Adrenergic stimulation promotes lipid mobilization and oxidation in brown and beige adipocytes, where the harnessed energy is dissipated as heat in a process known as adaptive thermogenesis. The signaling cascades and energy-dissipating pathways that facilitate thermogenesis have been extensively described, yet little is known about the counterbalancing negative regulatory mechanisms. Here, we identify a two-pore-domain potassium channel, KCNK3, as a built-in rheostat negatively regulating thermogenesis. Kcnk3 is transcriptionally wired into the thermogenic program by PRDM16, a master regulator of thermogenesis...
September 30, 2017: Cell
https://www.readbyqxmd.com/read/28965762/a-population-representation-of-absolute-light-intensity-in-the-mammalian-retina
#12
Elliott Scott Milner, Michael Tri Hoang Do
Environmental illumination spans many log units of intensity and is tracked for essential functions that include regulation of the circadian clock, arousal state, and hormone levels. Little is known about the neural representation of light intensity and how it covers the necessary range. This question became accessible with the discovery of mammalian photoreceptors that are required for intensity-driven functions, the M1 ipRGCs. The spike outputs of M1s are thought to uniformly track intensity over a wide range...
September 27, 2017: Cell
https://www.readbyqxmd.com/read/28965761/genomic-patterns-of-de-novo-mutation-in-simplex-autism
#13
Tychele N Turner, Bradley P Coe, Diane E Dickel, Kendra Hoekzema, Bradley J Nelson, Michael C Zody, Zev N Kronenberg, Fereydoun Hormozdiari, Archana Raja, Len A Pennacchio, Robert B Darnell, Evan E Eichler
To further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes >59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of ∼1.5 × 10(-8) SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends...
September 27, 2017: Cell
https://www.readbyqxmd.com/read/28965760/chemical-proteomics-identifies-druggable-vulnerabilities-in-a-genetically-defined-cancer
#14
Liron Bar-Peled, Esther K Kemper, Radu M Suciu, Ekaterina V Vinogradova, Keriann M Backus, Benjamin D Horning, Thomas A Paul, Taka-Aki Ichu, Robert U Svensson, Jose Olucha, Max W Chang, Bernard P Kok, Zhou Zhu, Nathan T Ihle, Melissa M Dix, Ping Jiang, Matthew M Hayward, Enrique Saez, Reuben J Shaw, Benjamin F Cravatt
The transcription factor NRF2 is a master regulator of the cellular antioxidant response, and it is often genetically activated in non-small-cell lung cancers (NSCLCs) by, for instance, mutations in the negative regulator KEAP1. While direct pharmacological inhibition of NRF2 has proven challenging, its aberrant activation rewires biochemical networks in cancer cells that may create special vulnerabilities. Here, we use chemical proteomics to map druggable proteins that are selectively expressed in KEAP1-mutant NSCLC cells...
September 27, 2017: Cell
https://www.readbyqxmd.com/read/28965759/temporal-control-of-mammalian-cortical-neurogenesis-by-m-6-a-methylation
#15
Ki-Jun Yoon, Francisca Rojas Ringeling, Caroline Vissers, Fadi Jacob, Michael Pokrass, Dennisse Jimenez-Cyrus, Yijing Su, Nam-Shik Kim, Yunhua Zhu, Lily Zheng, Sunghan Kim, Xinyuan Wang, Louis C Doré, Peng Jin, Sergi Regot, Xiaoxi Zhuang, Stefan Canzar, Chuan He, Guo-Li Ming, Hongjun Song
N(6)-methyladenosine (m(6)A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m(6)A regulates mammalian brain development is unknown. Here, we show that m(6)A depletion by Mettl14 knockout in embryonic mouse brains prolongs the cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m(6)A depletion by Mettl3 knockdown also leads to a prolonged cell cycle and maintenance of radial glia cells. m(6)A sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, the cell cycle, and neuronal differentiation, and m(6)A tagging promotes their decay...
September 25, 2017: Cell
https://www.readbyqxmd.com/read/28965758/parvalbumin-and-somatostatin-interneurons-control-different-space-coding-networks-in-the-medial-entorhinal-cortex
#16
Chenglin Miao, Qichen Cao, May-Britt Moser, Edvard I Moser
The medial entorhinal cortex (MEC) contains several discrete classes of GABAergic interneurons, but their specific contributions to spatial pattern formation in this area remain elusive. We employed a pharmacogenetic approach to silence either parvalbumin (PV)- or somatostatin (SOM)-expressing interneurons while MEC cells were recorded in freely moving mice. PV-cell silencing antagonized the hexagonally patterned spatial selectivity of grid cells, especially in layer II of MEC. The impairment was accompanied by reduced speed modulation in colocalized speed cells...
September 23, 2017: Cell
https://www.readbyqxmd.com/read/28942918/structure-of-fus-protein-fibrils-and-its-relevance-to-self-assembly-and-phase-separation-of-low-complexity-domains
#17
Dylan T Murray, Masato Kato, Yi Lin, Kent R Thurber, Ivan Hung, Steven L McKnight, Robert Tycko
Polymerization and phase separation of proteins containing low-complexity (LC) domains are important factors in gene expression, mRNA processing and trafficking, and localization of translation. We have used solid-state nuclear magnetic resonance methods to characterize the molecular structure of self-assembling fibrils formed by the LC domain of the fused in sarcoma (FUS) RNA-binding protein. From the 214-residue LC domain of FUS (FUS-LC), a segment of only 57 residues forms the fibril core, while other segments remain dynamically disordered...
September 21, 2017: Cell
https://www.readbyqxmd.com/read/28942924/excitable-dynamics-and-yap-dependent-mechanical-cues-drive-the-segmentation-clock
#18
Alexis Hubaud, Ido Regev, L Mahadevan, Olivier Pourquié
The periodic segmentation of the vertebrate body axis into somites, and later vertebrae, relies on a genetic oscillator (the segmentation clock) driving the rhythmic activity of signaling pathways in the presomitic mesoderm (PSM). To understand whether oscillations are an intrinsic property of individual cells or represent a population-level phenomenon, we established culture conditions for stable oscillations at the cellular level. This system was used to demonstrate that oscillations are a collective property of PSM cells that can be actively triggered in vitro by a dynamical quorum sensing signal involving Yap and Notch signaling...
September 20, 2017: Cell
https://www.readbyqxmd.com/read/28942923/transcriptional-architecture-of-synaptic-communication-delineates-gabaergic-neuron-identity
#19
Anirban Paul, Megan Crow, Ricardo Raudales, Miao He, Jesse Gillis, Z Josh Huang
Understanding the organizational logic of neural circuits requires deciphering the biological basis of neuronal diversity and identity, but there is no consensus on how neuron types should be defined. We analyzed single-cell transcriptomes of a set of anatomically and physiologically characterized cortical GABAergic neurons and conducted a computational genomic screen for transcriptional profiles that distinguish them from one another. We discovered that cardinal GABAergic neuron types are delineated by a transcriptional architecture that encodes their synaptic communication patterns...
September 20, 2017: Cell
https://www.readbyqxmd.com/read/28942922/age-dependent-alterations-in-meiotic-recombination-cause-chromosome-segregation-errors-in-spermatocytes
#20
Maciej J Zelazowski, Maria Sandoval, Lakshmi Paniker, Holly M Hamilton, Jiaying Han, Mikalah A Gribbell, Rhea Kang, Francesca Cole
Faithful chromosome segregation in meiosis requires crossover (CO) recombination, which is regulated to ensure at least one CO per homolog pair. We investigate the failure to ensure COs in juvenile male mice. By monitoring recombination genome-wide using cytological assays and at hotspots using molecular assays, we show that juvenile mouse spermatocytes have fewer COs relative to adults. Analysis of recombination in the absence of MLH3 provides evidence for greater utilization in juveniles of pathways involving structure-selective nucleases and alternative complexes, which can act upon precursors to generate noncrossovers (NCOs) at the expense of COs...
September 20, 2017: Cell
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