Cell

SnapShot: Nucleotide Excision Repair.

Publication Date: 2010 Mar 5 PMID: 20211143
Authors: Guo, C. - Tang, T. S. - Friedberg, E. C.
Journal: Cell

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An Atlas of Combinatorial Transcriptional Regulation in Mouse and Man.

Publication Date: 2010 Mar 5 PMID: 20211142
Authors: Ravasi, T. - Suzuki, H. - Cannistraci, C. V. - Katayama, S. - Bajic, V. B. - Tan, K. - Akalin, A. - Schmeier, S. - Kanamori-Katayama, M. - Bertin, N. - Carninci, P. - Daub, C. O. - Forrest, A. R. - Gough, J. - Grimmond, S. - Han, J. H. - Hashimoto, T. - Hide, W. - Hofmann, O. - Kawaji, H. - Kubosaki, A. - Lassmann, T. - van Nimwegen, E. - Ogawa, C. - Teasdale, R. D. - Tegner, J. - Lenhard, B. - Teichmann, S. A. - Arakawa, T. - Ninomiya, N. - Murakami, K. - Tagami, M. - Fukuda, S. - Imamura, K. - Kai, C. - Ishihara, R. - Kitazume, Y. - Kawai, J. - Hume, D. A. - Ideker, T. - Hayashizaki, Y.
Journal: Cell

Combinatorial interactions among transcription factors are critical to directing tissue-specific gene expression. To build a global atlas of these combinations, we have screened for physical interactions among the majority of human and mouse DNA-binding transcription factors (TFs). The complete networks contain 762 human and 877 mouse interactions. Analysis of the networks reveals that highly connected TFs are broadly expressed across tissues, and that roughly half of the measured interactions are conserved between mouse and human. The data highlight the importance of TF combinations for determining cell fate, and they lead to the identification of a SMAD3/FLI1 complex expressed during development of immunity. The availability of large TF combinatorial networks in both human and mouse will provide many opportunities to study gene regulation, tissue differentiation, and mammalian evolution.

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Genome-wide Analysis of the Host Intracellular Network that Regulates Survival of Mycobacterium tuberculosis.

Publication Date: 2010 Mar 5 PMID: 20211141
Authors: Kumar, D. - Nath, L. - Kamal, M. A. - Varshney, A. - Jain, A. - Singh, S. - Rao, K. V.
Journal: Cell

We performed a genome-wide siRNA screen to identify host factors that regulated pathogen load in human macrophages infected with a virulent strain of Mycobacterium tuberculosis. Iterative rounds of confirmation, followed by validation, identified 275 such molecules that were all found to functionally associate with each other through a dense network of interactions. This network then yielded to a molecular description of the host cell functional modules that were both engaged and perturbed by the pathogen. Importantly, a subscreen against a panel of field isolates revealed that the molecular composition of the host interface varied with both genotype and the phenotypic properties of the pathogen. An analysis of these differences, however, permitted identification of those host factors that were invariantly involved, regardless of the diversification in adaptive mechanisms employed by the pathogen. Interestingly, these factors were found to predominantly function through the regulation of autophagy.

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The lta4h Locus Modulates Susceptibility to Mycobacterial Infection in Zebrafish and Humans.

Publication Date: 2010 Mar 5 PMID: 20211140
Authors: Tobin, D. M. - Vary, J. C. Jr - Ray, J. P. - Walsh, G. S. - Dunstan, S. J. - Bang, N. D. - Hagge, D. A. - Khadge, S. - King, M. C. - Hawn, T. R. - Moens, C. B. - Ramakrishnan, L.
Journal: Cell

Exposure to Mycobacterium tuberculosis produces varied early outcomes, ranging from resistance to infection to progressive disease. Here we report results from a forward genetic screen in zebrafish larvae that identify multiple mutant classes with distinct patterns of innate susceptibility to Mycobacterium marinum. A hypersusceptible mutant maps to the lta4h locus encoding leukotriene A(4) hydrolase, which catalyzes the final step in the synthesis of leukotriene B(4) (LTB(4)), a potent chemoattractant and proinflammatory eicosanoid. lta4h mutations confer hypersusceptibility independent of LTB(4) reduction, by redirecting eicosanoid substrates to anti-inflammatory lipoxins. The resultant anti-inflammatory state permits increased mycobacterial proliferation by limiting production of tumor necrosis factor. In humans, we find that protection from both tuberculosis and multibacillary leprosy is associated with heterozygosity for LTA4H polymorphisms that have previously been correlated with differential LTB(4) production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.

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The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc.

Publication Date: 2010 Mar 5 PMID: 20211139
Authors: Greer, P. L. - Hanayama, R. - Bloodgood, B. L. - Mardinly, A. R. - Lipton, D. M. - Flavell, S. W. - Kim, T. K. - Griffith, E. C. - Waldon, Z. - Maehr, R. - Ploegh, H. L. - Chowdhury, S. - Worley, P. F. - Steen, J. - Greenberg, M. E.
Journal: Cell

Angelman Syndrome is a debilitating neurological disorder caused by mutation of the E3 ubiquitin ligase Ube3A, a gene whose mutation has also recently been associated with autism spectrum disorders (ASDs). The function of Ube3A during nervous system development and how Ube3A mutations give rise to cognitive impairment in individuals with Angleman Syndrome and ASDs are not clear. We report here that experience-driven neuronal activity induces Ube3A transcription and that Ube3A then regulates excitatory synapse development by controlling the degradation of Arc, a synaptic protein that promotes the internalization of the AMPA subtype of glutamate receptors. We find that disruption of Ube3A function in neurons leads to an increase in Arc expression and a concomitant decrease in the number of AMPA receptors at excitatory synapses. We propose that this deregulation of AMPA receptor expression at synapses may contribute to the cognitive dysfunction that occurs in Angelman Syndrome and possibly other ASDs.

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The Tetrahymena Argonaute-Binding Protein Giw1p Directs a Mature Argonaute-siRNA Complex to the Nucleus.

Publication Date: 2010 Mar 5 PMID: 20211138
Authors: Noto, T. - Kurth, H. M. - Kataoka, K. - Aronica, L. - Desouza, L. V. - Siu, K. W. - Pearlman, R. E. - Gorovsky, M. A. - Mochizuki, K.
Journal: Cell

Emerging evidence suggests that RNA interference (RNAi)-related processes act both in the cytoplasm and in the nucleus. However, the process by which the RNAi machinery is transported into the nucleus remains poorly understood. The Tetrahymena Argonaute protein Twi1p localizes to the nucleus and is crucial for small RNA-directed programmed DNA elimination. In this study, we identify Giw1p, which binds to Twi1p and is required for its nuclear localization. Furthermore, the endoribonuclease (Slicer) activity of Twi1p plays a vital role in the removal of one of the two strands of Twi1p-associated small interfering RNAs (siRNAs), leading to a functionally mature Twi1p-siRNA complex. Slicer activity is also shown to be required for nuclear localization of Twi1p and for its association with Giw1p. These results suggest that Giw1p senses the state of Twi1p-associated siRNAs and selectively transports the mature Twi1p-siRNA complex into the nucleus.

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Distinct Factors Control Histone Variant H3.3 Localization at Specific Genomic Regions.

Publication Date: 2010 Mar 5 PMID: 20211137
Authors: Goldberg, A. D. - Banaszynski, L. A. - Noh, K. M. - Lewis, P. W. - Elsaesser, S. J. - Stadler, S. - Dewell, S. - Law, M. - Guo, X. - Li, X. - Wen, D. - Chapgier, A. - Dekelver, R. C. - Miller, J. C. - Lee, Y. L. - Boydston, E. A. - Holmes, M. C. - Gregory, P. D. - Greally, J. M. - Rafii, S. - Yang, C. - Scambler, P. J. - Garrick, D. - Gibbons, R. J. - Higgs, D. R. - Cristea, I. M. - Urnov, F. D. - Zheng, D. - Allis, C. D.
Journal: Cell

The incorporation of histone H3 variants has been implicated in the epigenetic memory of cellular state. Using genome editing with zinc-finger nucleases to tag endogenous H3.3, we report genome-wide profiles of H3 variants in mammalian embryonic stem cells and neuronal precursor cells. Genome-wide patterns of H3.3 are dependent on amino acid sequence and change with cellular differentiation at developmentally regulated loci. The H3.3 chaperone Hira is required for H3.3 enrichment at active and repressed genes. Strikingly, Hira is not essential for localization of H3.3 at telomeres and many transcription factor binding sites. Immunoaffinity purification and mass spectrometry reveal that the proteins Atrx and Daxx associate with H3.3 in a Hira-independent manner. Atrx is required for Hira-independent localization of H3.3 at telomeres and for the repression of telomeric RNA. Our data demonstrate that multiple and distinct factors are responsible for H3.3 localization at specific genomic locations in mammalian cells.

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Stc1: A Critical Link between RNAi and Chromatin Modification Required for Heterochromatin Integrity.

Publication Date: 2010 Mar 5 PMID: 20211136
Authors: Bayne, E. H. - White, S. A. - Kagansky, A. - Bijos, D. A. - Sanchez-Pulido, L. - Hoe, K. L. - Kim, D. U. - Park, H. O. - Ponting, C. P. - Rappsilber, J. - Allshire, R. C.
Journal: Cell

In fission yeast, RNAi directs heterochromatin formation at centromeres, telomeres, and the mating type locus. Noncoding RNAs transcribed from repeat elements generate siRNAs that are incorporated into the Argonaute-containing RITS complex and direct it to nascent homologous transcripts. This leads to recruitment of the CLRC complex, including the histone methyltransferase Clr4, promoting H3K9 methylation and heterochromatin formation. A key question is what mediates the recruitment of Clr4/CLRC to transcript-bound RITS. We have identified a LIM domain protein, Stc1, that is required for centromeric heterochromatin integrity. Our analyses show that Stc1 is specifically required to establish H3K9 methylation via RNAi, and interacts both with the RNAi effector Ago1, and with the chromatin-modifying CLRC complex. Moreover, tethering Stc1 to a euchromatic locus is sufficient to induce silencing and heterochromatin formation independently of RNAi. We conclude that Stc1 associates with RITS on centromeric transcripts and recruits CLRC, thereby coupling RNAi to chromatin modification.

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miR-328 Functions as an RNA Decoy to Modulate hnRNP E2 Regulation of mRNA Translation in Leukemic Blasts.

Publication Date: 2010 Mar 5 PMID: 20211135
Authors: Eiring, A. M. - Harb, J. G. - Neviani, P. - Garton, C. - Oaks, J. J. - Spizzo, R. - Liu, S. - Schwind, S. - Santhanam, R. - Hickey, C. J. - Becker, H. - Chandler, J. C. - Andino, R. - Cortes, J. - Hokland, P. - Huettner, C. S. - Bhatia, R. - Roy, D. C. - Liebhaber, S. A. - Caligiuri, M. A. - Marcucci, G. - Garzon, R. - Croce, C. M. - Calin, G. A. - Perrotti, D.
Journal: Cell

MicroRNAs and heterogeneous ribonucleoproteins (hnRNPs) are posttranscriptional gene regulators that bind mRNA in a sequence-specific manner. Here, we report that loss of miR-328 occurs in blast crisis chronic myelogenous leukemia (CML-BC) in a BCR/ABL dose- and kinase-dependent manner through the MAPK-hnRNP E2 pathway. Restoration of miR-328 expression rescues differentiation and impairs survival of leukemic blasts by simultaneously interacting with the translational regulator poly(rC)-binding protein hnRNP E2 and with the mRNA encoding the survival factor PIM1, respectively. The interaction with hnRNP E2 is independent of the microRNA's seed sequence and it leads to release of CEBPA mRNA from hnRNP E2-mediated translational inhibition. Altogether, these data reveal the dual ability of a microRNA to control cell fate both through base pairing with mRNA targets and through a decoy activity that interferes with the function of regulatory proteins. PAPERFLICK:

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Protein Dynamics in Drug Combinations: a Linear Superposition of Individual-Drug Responses.

Publication Date: 2010 Mar 5 PMID: 20211134
Authors: Geva-Zatorsky, N. - Dekel, E. - Cohen, A. A. - Danon, T. - Cohen, L. - Alon, U.
Journal: Cell

Drugs and drug combinations have complex biological effects on cells and organisms. Little is known about how drugs affect protein dynamics that determine these effects. Here, we use a dynamic proteomics approach to accurately follow 15 protein levels in human cells in response to 13 different drugs. We find that protein dynamics in response to combinations of drugs are described accurately by a linear superposition (weighted sum) of their response to individual drugs. The weights in this superposition describe the relative impact of each drug on each protein. Using these weights, we show that one can predict the dynamics in a three-drug or four-drug combination on the basis of the dynamics in drug pairs. Our approach might eliminate the need to increase the number of experiments exponentially with the number of drugs and suggests that it might be possible to rationally control protein dynamics with specific drug combinations. PAPERCLIP:

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The Genome of Naegleria gruberi Illuminates Early Eukaryotic Versatility.

Publication Date: 2010 Mar 5 PMID: 20211133
Authors: Fritz-Laylin, L. K. - Prochnik, S. E. - Ginger, M. L. - Dacks, J. B. - Carpenter, M. L. - Field, M. C. - Kuo, A. - Paredez, A. - Chapman, J. - Pham, J. - Shu, S. - Neupane, R. - Cipriano, M. - Mancuso, J. - Tu, H. - Salamov, A. - Lindquist, E. - Shapiro, H. - Lucas, S. - Grigoriev, I. V. - Cande, W. Z. - Fulton, C. - Rokhsar, D. S. - Dawson, S. C.
Journal: Cell

Genome sequences of diverse free-living protists are essential for understanding eukaryotic evolution and molecular and cell biology. The free-living amoeboflagellate Naegleria gruberi belongs to a varied and ubiquitous protist clade (Heterolobosea) that diverged from other eukaryotic lineages over a billion years ago. Analysis of the 15,727 protein-coding genes encoded by Naegleria's 41 Mb nuclear genome indicates a capacity for both aerobic respiration and anaerobic metabolism with concomitant hydrogen production, with fundamental implications for the evolution of organelle metabolism. The Naegleria genome facilitates substantially broader phylogenomic comparisons of free-living eukaryotes than previously possible, allowing us to identify thousands of genes likely present in the pan-eukaryotic ancestor, with 40% likely eukaryotic inventions. Moreover, we construct a comprehensive catalog of amoeboid-motility genes. The Naegleria genome, analyzed in the context of other protists, reveals a remarkably complex ancestral eukaryote with a rich repertoire of cytoskeletal, sexual, signaling, and metabolic modules.

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Autoimmunity and the Clearance of Dead Cells.

Publication Date: 2010 Mar 5 PMID: 20211132
Authors: Nagata, S. - Hanayama, R. - Kawane, K.
Journal: Cell

To maintain organismal homeostasis, phagocytes engulf dead cells, which are recognized as dead by virtue of a characteristic "eat me" signal exposed on their surface. The dead cells are then transferred to lysosomes, where their cellular components are degraded for reuse. Inefficient engulfment of dead cells activates the immune system, causing disease such as systemic lupus erythematosus, and if the DNA of the dead cells is not properly degraded, the innate immune response becomes activated, leading to severe anemia and chronic arthritis. Here, we discuss how the endogenous components of dead cells activate the immune system through both extracellular and intracellular pathways.

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TB: Screening for Responses to a Vile Visitor.

Publication Date: 2010 Mar 5 PMID: 20211131
Authors: Behr, M. - Schurr, E. - Gros, P.
Journal: Cell

Mycobacteria, the pathogens that cause tuberculosis and leprosy, establish long-term infections in host macrophages. Recent studies, including two genetic screens reported in this issue of Cell (Kumar et al., 2010; Tobin et al., 2010), reveal that virulent mycobacteria evade the host immune system by stimulating production of anti-inflammatory molecules and inhibiting autophagy.

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MicroRNAs: From Decay to Decoy.

Publication Date: 2010 Mar 5 PMID: 20211130
Authors: Beitzinger, M. - Meister, G.
Journal: Cell

MicroRNAs interact with Argonaute proteins to guide posttranscriptional gene silencing. Eiring et al. (2010) now show that miR-328 has a second function, acting as a decoy by binding to hnRNP E2 and lifting its translational repression of an mRNA involved in myeloid cell differentiation.

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A Penetrating Look at Stochasticity in Development.

Publication Date: 2010 Mar 5 PMID: 20211129
Authors: Johnston, R. J. Jr - Desplan, C.
Journal: Cell

In recent work published in Nature, Raj et al. (2010) use single mRNA molecule quantification to show that variation in gene expression in Caenorhabditis elegans increases in mutants displaying incomplete penetrance. They find that a bimodal response is triggered when noisy expression of an upstream regulator crosses a critical threshold.

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Angelman Syndrome: Finding the Lost Arc.

Publication Date: 2010 Mar 5 PMID: 20211128
Authors: Tai, H. C. - Schuman, E. M.
Journal: Cell

Angelman syndrome is a neurodevelopmental disorder caused by mutations in the maternally inherited UBE3A gene, which encodes a ubiquitin ligase. Greer et al. (2010) now identify a UBE3A substrate called Arc that promotes endocytosis of neuronal AMPA receptors, providing insight into synaptic defects that may underlie the cognitive deficits in Angelman syndrome.

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The Incredible Expanding Ancestor of Eukaryotes.

Publication Date: 2010 Mar 5 PMID: 20211127
Authors: Koonin, E. V.
Journal: Cell

Comparing the genome sequences of free-living organisms in the five eukaryotic supergroups enables predictions to be made about the genome of the last common ancestor of eukaryotes. The genome sequence of the amoeboflagellate Naegleria gruberi reported by Fritz-Laylin et al. (2010) reveals the surprising complexity of this unicellular organism and, by inference, of the last common eukaryotic ancestor.

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Membrane Curvature in Synaptic Vesicle Fusion and Beyond.

Publication Date: 2010 Mar 5 PMID: 20211126
Authors: McMahon, H. T. - Kozlov, M. M. - Martens, S.
Journal: Cell

Recent evidence suggests that the Ca(2+)-sensors synaptotagmin-1 and Doc2b deform synaptic membranes during synaptic vesicle exocytosis. We discuss how local curvature generated by these and other proteins may stimulate membrane fusion and discuss the potential implications of these findings for other cellular fusion events.

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SnapShot: The unfolded protein response.

Publication Date: 2010 Feb 19 PMID: 20178750
Authors: Wiseman, R. L. - Haynes, C. M. - Ron, D.
Journal: Cell

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Forgetting is regulated through Rac activity in Drosophila.

Publication Date: 2010 Feb 19 PMID: 20178749
Authors: Shuai, Y. - Lu, B. - Hu, Y. - Wang, L. - Sun, K. - Zhong, Y.
Journal: Cell

Initially acquired memory dissipates rapidly if not consolidated. Such memory decay is thought to result either from the inherently labile nature of newly acquired memories or from interference by subsequently attained information. Here we report that a small G protein Rac-dependent forgetting mechanism contributes to both passive memory decay and interference-induced forgetting in Drosophila. Inhibition of Rac activity leads to slower decay of early memory, extending it from a few hours to more than one day, and to blockade of interference-induced forgetting. Conversely, elevated Rac activity in mushroom body neurons accelerates memory decay. This forgetting mechanism does not affect memory acquisition and is independent of Rutabaga adenylyl cyclase-mediated memory formation mechanisms. Endogenous Rac activation is evoked on different time scales during gradual memory loss in passive decay and during acute memory removal in reversal learning. We suggest that Rac's role in actin cytoskeleton remodeling may contribute to memory erasure. PAPERCLIP:

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Autophosphorylated CaMKIIalpha acts as a scaffold to recruit proteasomes to dendritic spines.

Publication Date: 2010 Feb 19 PMID: 20178748
Authors: Bingol, B. - Wang, C. F. - Arnott, D. - Cheng, D. - Peng, J. - Sheng, M.
Journal: Cell

The molecular mechanisms regulating the ubiquitin proteasome system (UPS) at synapses are poorly understood. We report that CaMKIIalpha-an abundant postsynaptic protein kinase-mediates the activity-dependent recruitment of proteasomes to dendritic spines in hippocampal neurons. CaMKIIalpha is biochemically associated with proteasomes in the brain. CaMKIIalpha translocation to synapses is required for activity-induced proteasome accumulation in spines, and is sufficient to redistribute proteasomes to postsynaptic sites. CaMKIIalpha autophosphorylation enhances its binding to proteasomes and promotes proteasome recruitment to spines. In addition to this structural role, CaMKIIalpha stimulates proteasome activity by phosphorylating proteasome subunit Rpt6 on Serine 120. However, CaMKIIalpha translocation, but not its kinase activity, is required for activity-dependent degradation of polyubiquitinated proteins in spines. Our findings reveal a scaffolding role of postsynaptic CaMKIIalpha in activity-dependent proteasome redistribution, which is commensurate with the great abundance of CaMKIIalpha in synapses.

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Nfix regulates fetal-specific transcription in developing skeletal muscle.

Publication Date: 2010 Feb 19 PMID: 20178747
Authors: Messina, G. - Biressi, S. - Monteverde, S. - Magli, A. - Cassano, M. - Perani, L. - Roncaglia, E. - Tagliafico, E. - Starnes, L. - Campbell, C. E. - Grossi, M. - Goldhamer, D. J. - Gronostajski, R. M. - Cossu, G.
Journal: Cell

Skeletal myogenesis, like hematopoiesis, occurs in successive developmental stages that involve different cell populations and expression of different genes. We show here that the transcription factor nuclear factor one X (Nfix), whose expression is activated by Pax7 in fetal muscle, in turn activates the transcription of fetal specific genes such as MCK and beta-enolase while repressing embryonic genes such as slow myosin. In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A. Premature expression of Nfix activates fetal and suppresses embryonic genes in embryonic muscle, whereas muscle-specific ablation of Nfix prevents fetal and maintains embryonic gene expression in the fetus. Therefore, Nfix acts as a transcriptional switch from embryonic to fetal myogenesis.

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Actin dynamics drive membrane reorganization and scission in clathrin-independent endocytosis.

Publication Date: 2010 Feb 19 PMID: 20178746
Authors: Romer, W. - Pontani, L. L. - Sorre, B. - Rentero, C. - Berland, L. - Chambon, V. - Lamaze, C. - Bassereau, P. - Sykes, C. - Gaus, K. - Johannes, L.
Journal: Cell

Nascent transport intermediates detach from donor membranes by scission. This process can take place in the absence of dynamin, notably in clathrin-independent endocytosis, by mechanisms that are yet poorly defined. We show here that in cells scission of Shiga toxin-induced tubular endocytic membrane invaginations is preceded by cholesterol-dependent membrane reorganization and correlates with the formation of membrane domains on model membranes, suggesting that domain boundary forces are driving tubule membrane constriction. Actin triggers scission by inducing such membrane reorganization process. Tubule occurrence is indeed increased upon cellular depletion of the actin nucleator component Arp2, and the formation of a cortical actin shell in liposomes is sufficient to trigger the scission of Shiga toxin-induced tubules in a cholesterol-dependent but dynamin-independent manner. Our study suggests that membranes in tubular Shiga toxin-induced invaginations are poised to undergo actin-triggered reorganization leading to scission by a physical mechanism that may function independently from or in synergy with pinchase activity. PAPERFLICK:

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Elevated ATPase activity of KaiC applies a circadian checkpoint on cell division in Synechococcus elongatus.

Publication Date: 2010 Feb 19 PMID: 20178745
Authors: Dong, G. - Yang, Q. - Wang, Q. - Kim, Y. I. - Wood, T. L. - Osteryoung, K. W. - van Oudenaarden, A. - Golden, S. S.
Journal: Cell

A circadian clock coordinates physiology and behavior in diverse groups of living organisms. Another major cyclic cellular event, the cell cycle, is regulated by the circadian clock in the few cases where linkage of these cycles has been studied. In the cyanobacterium Synechococcus elongatus, the circadian clock gates cell division by an unknown mechanism. Using timelapse microscopy, we confirm the gating of cell division in the wild-type and demonstrate the regulation of cytokinesis by key clock components. Specifically, a state of the oscillator protein KaiC that is associated with elevated ATPase activity closes the gate by acting through a known clock output pathway to inhibit FtsZ ring formation at the division site. An activity that stimulates KaiC phosphorylation independently of the KaiA protein was also uncovered. We propose a model that separates the functions of KaiC ATPase and phosphorylation in cell division gating and other circadian behaviors.

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Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling.

Publication Date: 2010 Feb 19 PMID: 20178744
Authors: Woo, H. A. - Yim, S. H. - Shin, D. H. - Kang, D. - Yu, D. Y. - Rhee, S. G.
Journal: Cell

Despite its toxicity, H(2)O(2) is produced as a signaling molecule that oxidizes critical cysteine residues of effectors such as protein tyrosine phosphatases in response to activation of cell surface receptors. It has remained unclear, however, how H(2)O(2) concentrations above the threshold required to modify effectors are achieved in the presence of the abundant detoxification enzymes peroxiredoxin (Prx) I and II. We now show that PrxI associated with membranes is transiently phosphorylated on tyrosine-194 and thereby inactivated both in cells stimulated via growth factor or immune receptors in vitro and in those at the margin of healing cutaneous wounds in mice. The localized inactivation of PrxI allows for the transient accumulation of H(2)O(2) around membranes, where signaling components are concentrated, while preventing the toxic accumulation of H(2)O(2) elsewhere. In contrast, PrxII was inactivated not by phosphorylation but rather by hyperoxidation of its catalytic cysteine during sustained oxidative stress.

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Dicer-independent primal RNAs trigger RNAi and heterochromatin formation.

Publication Date: 2010 Feb 19 PMID: 20178743
Authors: Halic, M. - Moazed, D.
Journal: Cell

Assembly of fission yeast pericentromeric heterochromatin and generation of small interfering RNAs (siRNAs) from noncoding centromeric transcripts are mutually dependent processes. How this interdependent positive feedback loop is first triggered is a fundamental unanswered question. Here, we show that two distinct Argonaute (Ago1)-dependent pathways mediate small RNA generation. RNA-dependent RNA polymerase complex (RDRC) and Dicer act on specific noncoding RNAs to generate siRNAs by a mechanism that requires the slicer activity of Ago1 but is independent of pre-existing heterochromatin. In the absence of RDRC or Dicer, a distinct class of small RNAs, called primal small RNAs (priRNAs), associates with Ago1. priRNAs are degradation products of abundant transcripts, which bind to Ago1 and target antisense transcripts that result from bidirectional transcription of DNA repeats. Our results suggest that a transcriptome surveillance mechanism based on random association of RNA degradation products with Argonaute triggers siRNA amplification and heterochromatin assembly within DNA repeats.

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The human PAF1 complex acts in chromatin transcription elongation both independently and cooperatively with SII/TFIIS.

Publication Date: 2010 Feb 19 PMID: 20178742
Authors: Kim, J. - Guermah, M. - Roeder, R. G.
Journal: Cell

Genetic and cell-based studies have implicated the PAF1 complex (PAF1C) in transcription-associated events, but there has been no evidence showing a direct role in facilitating transcription of a natural chromatin template. Here, we demonstrate an intrinsic ability of human PAF1C (hPAF1C) to facilitate activator (p53)- and histone acetyltransferase (p300)-dependent transcription elongation from a recombinant chromatin template in a biochemically defined RNA polymerase II transcription system. This represents a PAF1C function distinct from its established role in histone ubiquitylation and methylation. Importantly, we further demonstrate a strong synergy between hPAF1C and elongation factor SII/TFIIS and an underlying mechanism involving direct hPAF1C-SII interactions and cooperative binding to RNA polymerase II. Apart from a distinct PAF1C function, the present observations provide a molecular mechanism for the cooperative function of distinct transcription elongation factors in chromatin transcription.

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Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus.

Publication Date: 2010 Feb 19 PMID: 20178741
Authors: Li, W. - You, L. - Cooper, J. - Schiavon, G. - Pepe-Caprio, A. - Zhou, L. - Ishii, R. - Giovannini, M. - Hanemann, C. O. - Long, S. B. - Erdjument-Bromage, H. - Zhou, P. - Tempst, P. - Giancotti, F. G.
Journal: Cell

Current models imply that the FERM domain protein Merlin, encoded by the tumor suppressor NF2, inhibits mitogenic signaling at or near the plasma membrane. Here, we show that the closed, growth-inhibitory form of Merlin accumulates in the nucleus, binds to the E3 ubiquitin ligase CRL4(DCAF1), and suppresses its activity. Depletion of DCAF1 blocks the promitogenic effect of inactivation of Merlin. Conversely, enforced expression of a Merlin-insensitive mutant of DCAF1 counteracts the antimitogenic effect of Merlin. Re-expression of Merlin and silencing of DCAF1 implement a similar, tumor-suppressive program of gene expression. Tumor-derived mutations invariably disrupt Merlin's ability to interact with or inhibit CRL4(DCAF1). Finally, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. We propose that Merlin suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4(DCAF1).

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Lymphangiogenesis: Molecular mechanisms and future promise.

Publication Date: 2010 Feb 19 PMID: 20178740
Authors: Tammela, T. - Alitalo, K.
Journal: Cell

The growth of lymphatic vessels (lymphangiogenesis) is actively involved in a number of pathological processes including tissue inflammation and tumor dissemination but is insufficient in patients suffering from lymphedema, a debilitating condition characterized by chronic tissue edema and impaired immunity. The recent explosion of knowledge on the molecular mechanisms governing lymphangiogenesis provides new possibilities to treat these diseases.

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Circadian cell-cycle progression: Cracking open the gate.

Publication Date: 2010 Feb 19 PMID: 20178739
Authors: Morf, J. - Schibler, U.
Journal: Cell

In cyanobacteria cell division is intimately linked with the circadian cycle. Dong et al. (2010) now identify components of the circadian clock that regulate the formation of the midcell ring for cytokinesis, revealing a critical link between the circadian cycle and the control of cell division.

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Rac in the act of forgetting.

Publication Date: 2010 Feb 19 PMID: 20178738
Authors: Davis, R. L.
Journal: Cell

Forgetting has been thought to occur as a result of the natural decay of the neuronal changes induced by learning or because of interference from other cognitive functions. In this issue, Shuai et al. (2010) find that the small G protein Rac may function as a switch for remembering versus forgetting.

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Reining in H(2)O(2) for safe signaling.

Publication Date: 2010 Feb 19 PMID: 20178737
Authors: Toledano, M. B. - Planson, A. G. - Delaunay-Moisan, A.
Journal: Cell

Mammalian cells use hydrogen peroxide (H(2)O(2)) not only to kill invading pathogens, but also as a signaling modulator. Woo et al. (2010) now show that the local inactivation of a H(2)O(2)-degrading enzyme ensures that the production of this oxidant is restricted to the signaling site.

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Primal RNAs: The end of the beginning?

Publication Date: 2010 Feb 19 PMID: 20178736
Authors: Conte, D. Jr - Mello, C. C.
Journal: Cell

The amplification of small RNAs and the assembly of heterochromatin are mutually dependent processes in fission yeast. But which comes first? Halic and Moazed (2010) propose that primal small RNAs initiate the amplification of small interfering RNAs that drive heterochromatin formation and chromatin silencing.

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Lin28: A microRNA regulator with a macro role.

Publication Date: 2010 Feb 19 PMID: 20178735
Authors: Viswanathan, S. R. - Daley, G. Q.
Journal: Cell

Lin28, a highly conserved RNA-binding protein, has emerged as a modulator of the processing of the let-7 microRNA. This role for Lin28 has important implications for our mechanistic understanding of pluripotency, the timing of development, and oncogenesis.

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