EMBO Reports

El Sur tambien existe: processing RNA in the Argentine Patagonia. Meetings on 'Cell Biology, Signaling and Alternative Splicing' and 'Gene Expression and RNA Processing'

Publication Date: 2008 May 9 PMID: 18464796
Authors: Martinez, J. - Neugebauer, K. M.
Journal: EMBO Rep

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Switching of chromatin-remodelling complexes for oestrogen receptor-alpha.

Publication Date: 2008 May 2 PMID: 18451880
Authors: Okada, M. - Takezawa, S. I. - Mezaki, Y. - Yamaoka, I. - Takada, I. - Kitagawa, H. - Kato, S.
Journal: EMBO Rep

The female sex steroid hormone oestrogen stimulates both cell proliferation and cell differentiation in target tissues. These biological actions are mediated primarily through nuclear oestrogen receptors (ERs). The ligand-dependent transactivation of ERs requires several nuclear co-regulator complexes; however, the cell-cycle-dependent associations of these complexes are poorly understood. By using a synchronization system, we found that the transactivation function of ERalpha at G2/M was lowered. Biochemical approaches showed that ERalpha associated with two discrete classes of ATP-dependent chromatin-remodelling complex in a cell-cycle-dependent manner. The components of the NuRD-type complex were identified as G2/M-phase-specific ERalpha co-repressors. Thus, our results indicate that the transactivation function of ERalpha is cell-cycle dependent and is coupled with a cell-cycle-dependent association of chromatin-remodelling complexes.

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Atrophin recruits HDAC1/2 and G9a to modify histone H3K9 and to determine cell fates.

Publication Date: 2008 May 2 PMID: 18451879
Authors: Wang, L. - Charroux, B. - Kerridge, S. - Tsai, C. C.
Journal: EMBO Rep

Atrophin family proteins, including the vertebrate arginine-glutamic acid dipeptide repeats protein (RERE) and Drosophila Atrophin (Atro), constitute a new class of nuclear receptor corepressors. Both RERE and Atro share the ELM2 (EGL-27 and MTA1 homology 2) and SANT (SWI3/ADA2/N-CoR/TFIII-B) domains, which are also present in other important transcriptional cofactors. Here, we report that the SANT domain in RERE binds to the histone methyltransferase G9a, and that both the ELM2 and SANT domains orchestrate molecular events that lead to a stable methylation of histone H3-lysine 9. We establish the physiological relevance of these interactions among Atrophin, G9a, and histone deacetylases 1 and 2 in Drosophila by showing that these proteins localize to overlapping chromosomal loci, and act together to suppress wing vein and melanotic-mass formation. This study not only shows a new function of the SANT domain and establishes its connection with the ELM2 domain, but also implies that a similar strategy is used by other ELM2-SANT proteins to repress gene transcription and to exert biological effects.

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A transcription cofactor required for the heat-shock response.

Publication Date: 2008 May 2 PMID: 18451878
Authors: Xu, D. - Zalmas, L. P. - La Thangue, N. B.
Journal: EMBO Rep

The Stress-responsive activator of p300 (Strap) is a transcription cofactor that has an important role in the control of DNA damage response through its ability to regulate p53 activity. Here, we report that Strap is inducible by heat shock and stimulates the transcription of heat-shock genes. A chromatin-associated complex involving heat-shock factor 1 (HSF1), Strap and the p300 coactivator assembles on the heat-shock protein 70 (hsp70) promoter, and Strap augments HSF1 binding and chromatin acetylation in Hsp genes, most probably through the p300 histone acetyltransferase. Cells depleted of Strap do not survive under heat-shock conditions. These results indicate that Strap is an essential cofactor that acts at the level of chromatin control to regulate heat-shock-responsive transcription.

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Ion channels: functional expression and therapeutic potential in cancer. Colloquium on Ion Channels and Cancer.

Publication Date: 2008 May 2 PMID: 18451877
Authors: Fraser, S. P. - Pardo, L. A.
Journal: EMBO Rep

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No single way to understand singlet oxygen signalling in plants.

Publication Date: 2008 May PMID: 18451767
Authors: Kim, C. - Meskauskiene, R. - Apel, K. - Laloi, C.
Journal: EMBO Rep

When plant cells are under environmental stress, several chemically distinct reactive oxygen species (ROS) are generated simultaneously in various intracellular compartments and these can cause oxidative damage or act as signals. The conditional flu mutant of Arabidopsis, which generates singlet oxygen in plastids during a dark-to-light transition, has allowed the biological activity of singlet oxygen to be determined, and the criteria to distinguish between cytotoxicity and signalling of this particular ROS to be defined. The genetic basis of singlet-oxygen-mediated signalling has been revealed by the mutation of two nuclear genes encoding the plastid proteins EXECUTER (EX)1 and EX2, which are sufficient to abrogate singlet-oxygen-dependent stress responses. Conversely, responses due to higher cytotoxic levels of singlet oxygen are not suppressed in the ex1/ex2 background. Whether singlet oxygen levels lower than those that trigger genetically controlled cell death activate acclimation is now under investigation.

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PeptideAtlas: a resource for target selection for emerging targeted proteomics workflows.

Publication Date: 2008 May PMID: 18451766
Authors: Deutsch, E. W. - Lam, H. - Aebersold, R.
Journal: EMBO Rep

A crucial part of a successful systems biology experiment is an assay that provides reliable, quantitative measurements for each of the components in the system being studied. For proteomics to be a key part of such studies, it must deliver accurate quantification of all the components in the system for each tested perturbation without any gaps in the data. This will require a new approach to proteomics that is based on emerging targeted quantitative mass spectrometry techniques. The PeptideAtlas Project comprises a growing, publicly accessible database of peptides identified in many tandem mass spectrometry proteomics studies and software tools that allow the building of PeptideAtlas, as well as its use by the research community. Here, we describe the PeptideAtlas Project, its contents and components, and show how together they provide a unique platform to select and validate mass spectrometry targets, thereby allowing the next revolution in proteomics.

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Paths to acceptance. The advancement of scientific knowledge is an uphill struggle against 'accepted wisdom'.

Publication Date: 2008 May PMID: 18451765
Authors: Wolinsky, H.
Journal: EMBO Rep

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We are what we eat. The link between diet, evolution and non-genetic inheritance.

Publication Date: 2008 May PMID: 18451764
Authors: Hunter, P.
Journal: EMBO Rep

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The grand impact of the Gates Foundation. Sixty billion dollars and one famous person can affect the spending and research focus of public agencies.

Publication Date: 2008 May PMID: 18451763
Authors: Matthews, K. R. - Ho, V.
Journal: EMBO Rep

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An open challenge. Open access and the challenges for scientific publishing.

Publication Date: 2008 May PMID: 18451762
Authors: Bosch, X.
Journal: EMBO Rep

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Comment in response to 'A question of method' by Samia A. Hurst & Alex Mauron.

Publication Date: 2008 May PMID: 18451761
Authors: Rylander, R.
Journal: EMBO Rep

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Response by samia a. Hurst & alex mauron.

Publication Date: 2008 May PMID: 18451760
Authors: Hurst, S. A. - Mauron, A.
Journal: EMBO Rep

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Paralysed by perfection.

Publication Date: 2008 May PMID: 18451759
Authors: Gannon, F.
Journal: EMBO Rep

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Assembly of the three small Tim proteins precedes docking to the mitochondrial carrier translocase.

Publication Date: 2008 Apr 18 PMID: 18421298
Authors: Gebert, N. - Chacinska, A. - Wagner, K. - Guiard, B. - Koehler, C. M. - Rehling, P. - Pfanner, N. - Wiedemann, N.
Journal: EMBO Rep

The mitochondrial intermembrane space contains a family of small Tim proteins that function as essential chaperones for protein import. The soluble Tim9-Tim10 complex transfers hydrophobic precursor proteins through the aqueous intermembrane space to the carrier translocase of the inner membrane (TIM22 complex). Tim12, a peripheral membrane subunit of the TIM22 complex, is thought to recruit a portion of Tim9-Tim10 to the inner membrane. It is not known, however, how Tim12 is assembled. We have identified a new intermediate in the biogenesis pathway of Tim12. A soluble form of Tim12 first assembles with Tim9 and Tim10 to form a Tim12-core complex. Tim12-core then docks onto the membrane-integrated subunits of the TIM22 complex to form the holo-translocase. Thus, the function of Tim12 in linking soluble and membrane-integrated subunits of the import machinery involves a sequential assembly mechanism of the translocase through a soluble intermediate complex of the three essential small Tim proteins.

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The histone-binding protein COPR5 is required for nuclear functions of the protein arginine methyltransferase PRMT5.

Publication Date: 2008 May PMID: 18404153
Authors: Lacroix, M. - Messaoudi, S. E. - Rodier, G. - Le Cam, A. - Sardet, C. - Fabbrizio, E.
Journal: EMBO Rep

Protein arginine methyltransferase 5 (PRMT5) targets nuclear and cytoplasmic proteins. Here, we identified a nuclear protein, called cooperator of PRMT5 (COPR5), involved in the nuclear functions of PRMT5. COPR5 tightly binds to PRMT5, both in vitro and in living cells, but not to other members of the PRMT family. PRMT5 bound to COPR5 methylates histone H4 (R3) preferentially when compared with histone H3 (R8), suggesting that COPR5 modulates the substrate specificity of nuclear PRMT5-containing complexes, at least towards histones. Markedly, recombinant COPR5 binds to the amino terminus of histone H4 and is required to recruit PRMT5 to reconstituted nucleosomes in vitro. Consistently, COPR5 depletion in cells strongly reduces PRMT5 recruitment on chromatin at the PRMT5 target gene cyclin E1 (CCNE1) in vivo. Moreover, both COPR5 depletion and overexpression affect CCNE1 promoter expression. We propose that COPR5 is an important chromatin adaptor for PRMT5 to function on a subset of its target genes.

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To the centre of the volcano. Workshop on the mechanisms of nucleocytoplasmic transport.

Publication Date: 2008 May PMID: 18404152
Authors: Fornerod, M. - Clarke, P. R.
Journal: EMBO Rep

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Science amongst the vines. Meeting on signalling systems.

Publication Date: 2008 May PMID: 18404151
Authors: Pitson, S. M. - Goodall, G. J. - Guthridge, M. A.
Journal: EMBO Rep

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'Insulator bodies' are aggregates of proteins but not of insulators.

Publication Date: 2008 May PMID: 18369369
Authors: Golovnin, A. - Melnikova, L. - Volkov, I. - Kostuchenko, M. - Galkin, A. V. - Georgiev, P.
Journal: EMBO Rep

Chromatin insulators are thought to restrict the action of enhancers and silencers. The best-known insulators in Drosophila require proteins such as Suppressor of Hairy wing (Su(Hw)) and Modifier of mdg4 (Mod(mdg4)) to be functional. The insulator-related proteins apparently colocalize as nuclear speckles in immunostained cells. It has been asserted that these speckles are 'insulator bodies' of many Su(Hw)-insulator DNA sites held together by associated proteins, including Mod(mdg4). As we show here using flies, larvae and S2 cells, a mutant Mod(mdg4) protein devoid of the Q-rich domain supports the function of Su(Hw)-dependent insulators and efficiently binds to correct insulator sites on the chromosome, but does not form or enter the Su(Hw)-marked nuclear speckles; conversely, the latter accumulate another (C-truncated) Mod(mdg4) mutant that cannot interact with Su(Hw) or with the genuine insulators. Hence, it is not the functional genomic insulators but rather aggregated proteins that make the so-called 'insulator bodies'.

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Substrate-induced DNA strand misalignment during catalytic cycling by DNA polymerase lambda.

Publication Date: 2008 May PMID: 18369368
Authors: Bebenek, K. - Garcia-Diaz, M. - Foley, M. C. - Pedersen, L. C. - Schlick, T. - Kunkel, T. A.
Journal: EMBO Rep

The simple deletion of nucleotides is common in many organisms. It can be advantageous when it activates genes beneficial to microbial survival in adverse environments, and deleterious when it mutates genes relevant to survival, cancer or degenerative diseases. The classical idea is that simple deletions arise by strand slippage. A prime opportunity for slippage occurs during DNA synthesis, but it remains unclear how slippage is controlled during a polymerization cycle. Here, we report crystal structures and molecular dynamics simulations of mutant derivatives of DNA polymerase lambda bound to a primer-template during strand slippage. Relative to the primer strand, the template strand is in multiple conformations, indicating intermediates on the pathway to deletion mutagenesis. Consistent with these intermediates, the mutant polymerases generate single-base deletions at high rates. The results indicate that dNTP-induced template strand repositioning during conformational rearrangements in the catalytic cycle is crucial to controlling the rate of strand slippage.

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NMD resulting from encephalomyocarditis virus IRES-directed translation initiation seems to be restricted to CBP80/20-bound mRNA.

Publication Date: 2008 May PMID: 18369367
Authors: Woeller, C. F. - Gaspari, M. - Isken, O. - Maquat, L. E.
Journal: EMBO Rep

Nonsense-mediated messenger RNA decay (NMD) generally degrades mRNAs that prematurely terminate translation as a means of quality control. NMD in mammalian cells targets newly spliced mRNA that is bound by the cap-binding protein heterodimer CBP80/20 and one or more post-splicing exon junction complexes during a pioneer round of translation. NMD targets mRNA that initiates translation using the encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES), therefore NMD might target not only CBP80/20-bound mRNA but also its remodelled product, eIF4E-bound mRNA. Here, we provide evidence that NMD triggered by translation initiation at the EMCV IRES, similar to NMD triggered by translation initiation at an mRNA cap, targets CBP80/20-bound mRNA but does not detectably target eIF4E-bound mRNA. We show that EMCV IRES-initiated translation undergoes a CBP80/20-associated pioneer round of translation that results in CBP80/20-dependent and Upf factor-dependent NMD when translation terminates prematurely.

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Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts from mice with collagen-induced arthritis.

Publication Date: 2008 May PMID: 18369366
Authors: Gao, B. - Lee, S. M. - Chen, A. - Zhang, J. - Zhang, D. D. - Kannan, K. - Ortmann, R. A. - Fang, D.
Journal: EMBO Rep

The E3 ubiquitin ligase synoviolin (SYVN1) functions as an anti-apoptotic factor that is responsible for the outgrowth of synovial cells during the development of rheumatoid arthritis. The molecular mechanisms underlying SYVN1 regulation of cell death are largely unknown. Here, we report that elevated SYVN1 expression correlates with decreased levels of the protein inositol-requiring enzyme 1 (IRE1)-a pro-apoptotic factor in the endoplasmic reticulum (ER)-stress-induced apoptosis pathway-in synovial fibroblasts from mice with collagen-induced arthritis (CIA). SYVN1 interacts with and catalyses IRE1 ubiquitination and consequently promotes IRE1 degradation. Suppression of SYVN1 expression in synovial fibroblasts from CIA mice restores IRE1 protein expression and reverses the resistance of ER-stress-induced apoptosis of CIA synovial fibroblasts. These results show that SYVN1 causes the overgrowth of synovial cells by degrading IRE1, and therefore antagonizes ER-stress-induced cell death.

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Gene induction following wounding of wild-type versus macrophage-deficient Drosophila embryos.

Publication Date: 2008 May PMID: 18344972
Authors: Stramer, B. - Winfield, M. - Shaw, T. - Millard, T. H. - Woolner, S. - Martin, P.
Journal: EMBO Rep

By using a microarray screen to compare gene responses after sterile laser wounding of wild-type and 'macrophageless' serpent mutant Drosophila embryos, we show the wound-induced programmes that are independent of a pathogenic response and distinguish which of the genes are macrophage dependent. The evolutionarily conserved nature of this response is highlighted by our finding that one such new inflammation-associated gene, growth arrest and DNA damage-inducible gene 45 (GADD45), is upregulated in both Drosophila and murine repair models. Comparison of unwounded wild-type and serpent mutant embryos also shows a portfolio of 'macrophage-specific' genes, which suggest analogous functions with vertebrate inflammatory cells. Besides identifying the various classes of wound- and macrophage-related genes, our data indicate that sterile injury per se, in the absence of pathogens, triggers induction of a 'pathogen response', which might prime the organism for what is likely to be an increased risk of infection.

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NEDD8 acts as a 'molecular switch' defining the functional selectivity of VHL.

Publication Date: 2008 May PMID: 18323857
Authors: Russell, R. C. - Ohh, M.
Journal: EMBO Rep

The von Hippel-Lindau (VHL) tumour suppressor protein is important in the E3 ubiquitin ligase ECV (Elongin B/C-CUL2-VHL)-mediated destruction of hypoxia-inducible factor and the promotion of fibronectin (FN) extracellular matrix assembly. Although the precise molecular mechanism controlling the selectivity of VHL function remains unknown, a failure in either process is associated with oncogenic progression. Here, we show that VHL performs its FN-associated function independently of the ECV complex, highlighting the autonomy of these pathways. Furthermore, we show that NEDD8, a ubiquitin-like molecule, acts as a 'molecular switch' in which its covalent conjugation to VHL prohibits the engagement of the scaffold component CUL2 and, concomitantly, activates the association with FN. These findings provide the first mechanistic step in defining the functional selectivity of VHL and explain a previously unrecognized function of NEDD8.

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Formation of a new receptor-operated channel by heteromeric assembly of TRPP2 and TRPC1 subunits.

Publication Date: 2008 May PMID: 18323855
Authors: Bai, C. X. - Giamarchi, A. - Rodat-Despoix, L. - Padilla, F. - Downs, T. - Tsiokas, L. - Delmas, P.
Journal: EMBO Rep

Although several protein-protein interactions have been reported between transient receptor potential (TRP) channels, they are all known to occur exclusively between members of the same group. The only intergroup interaction described so far is that of TRPP2 and TRPC1; however, the significance of this interaction is unknown. Here, we show that TRPP2 and TRPC1 assemble to form a channel with a unique constellation of new and TRPP2/TRPC1-specific properties. TRPP2/TRPC1 is activated in response to G-protein-coupled receptor activation and shows a pattern of single-channel conductance, amiloride sensitivity and ion permeability distinct from that of TRPP2 or TRPC1 alone. Native TRPP2/TRPC1 activity is shown in kidney cells by complementary gain-of-function and loss-of-function experiments, and its existence under physiological conditions is supported by colocalization at the primary cilium and by co-immunoprecipitation from kidney membranes. Identification of the heteromultimeric TRPP2/TRPC1 channel has implications in mechanosensation and cilium-based Ca(2+) signalling.

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