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EMBO Reports

Fani-Marlen Roumelioti, Sotirios K Sotiriou, Vasiliki Katsini, Maria Chiourea, Thanos D Halazonetis, Sarantis Gagos
Human malignancies overcome replicative senescence either by activating the reverse-transcriptase telomerase or by utilizing a homologous recombination-based mechanism, referred to as alternative lengthening of telomeres (ALT). In budding yeast, ALT exhibits features of break-induced replication (BIR), a repair pathway for one-ended DNA double-strand breaks (DSBs) that requires the non-essential subunit Pol32 of DNA polymerase delta and leads to conservative DNA replication. Here, we examined whether ALT in human cancers also exhibits features of BIR A telomeric fluorescence in situ hybridization protocol involving three consecutive staining steps revealed the presence of conservatively replicated telomeric DNA in telomerase-negative cancer cells...
October 19, 2016: EMBO Reports
Toshifumi Fukuda, Shun Nagashima, Takaya Abe, Hiroshi Kiyonari, Ryoko Inatome, Shigeru Yanagi
The DISC1-interacting protein CAMDI has been suggested to promote radial migration through centrosome regulation. However, its physiological relevance is unclear. Here, we report the generation and characterization of CAMDI-deficient mice. CAMDI-deficient mice exhibit delayed radial migration with aberrant neural circuit formation and psychiatric behaviors including hyperactivity, repetitive behavior, and social abnormality typically observed in autism spectrum disorder patients. Analyses of direct targets of CAMDI identify HDAC6 whose α-tubulin deacetylase activity is inhibited by CAMDI at the centrosome...
October 13, 2016: EMBO Reports
Timothy Wai, Shotaro Saita, Hendrik Nolte, Sebastian Müller, Tim König, Ricarda Richter-Dennerlein, Hans-Georg Sprenger, Joaquin Madrenas, Mareike Mühlmeister, Ulrich Brandt, Marcus Krüger, Thomas Langer
The SPFH (stomatin, prohibitin, flotillin, HflC/K) superfamily is composed of scaffold proteins that form ring-like structures and locally specify the protein-lipid composition in a variety of cellular membranes. Stomatin-like protein 2 (SLP2) is a member of this superfamily that localizes to the mitochondrial inner membrane (IM) where it acts as a membrane organizer. Here, we report that SLP2 anchors a large protease complex composed of the rhomboid protease PARL and the i-AAA protease YME1L, which we term the SPY complex (for SLP2-PARL-YME1L)...
October 13, 2016: EMBO Reports
Ophélia Le Thuc, Céline Cansell, Miled Bourourou, Raphaël Gp Denis, Katharina Stobbe, Nadège Devaux, Alice Guyon, Julie Cazareth, Catherine Heurteaux, William Rostène, Serge Luquet, Nicolas Blondeau, Jean-Louis Nahon, Carole Rovère
Sickness behavior defines the endocrine, autonomic, behavioral, and metabolic responses associated with infection. While inflammatory responses were suggested to be instrumental in the loss of appetite and body weight, the molecular underpinning remains unknown. Here, we show that systemic or central lipopolysaccharide (LPS) injection results in specific hypothalamic changes characterized by a precocious increase in the chemokine ligand 2 (CCL2) followed by an increase in pro-inflammatory cytokines and a decrease in the orexigenic neuropeptide melanin-concentrating hormone (MCH)...
October 12, 2016: EMBO Reports
Remco Nagel, Ekaterina A Semenova, Anton Berns
Historically, cancers have been treated with chemotherapeutics aimed to have profound effects on tumor cells with only limited effects on normal tissue. This approach was followed by the development of small-molecule inhibitors that can target oncogenic pathways critical for the survival of tumor cells. The clinical targeting of these so-called oncogene addictions, however, is in many instances hampered by the outgrowth of resistant clones. More recently, the proper functioning of non-mutated genes has been shown to enhance the survival of many cancers, a phenomenon called non-oncogene addiction...
October 4, 2016: EMBO Reports
Tomoko Asaoka, Jorge Almagro, Christine Ehrhardt, Isabella Tsai, Alexander Schleiffer, Luiza Deszcz, Sini Junttila, Leonie Ringrose, Karl Mechtler, Anoop Kavirayani, Attila Gyenesei, Kay Hofmann, Peter Duchek, Katrin Rittinger, Fumiyo Ikeda
The HOIP ubiquitin E3 ligase generates linear ubiquitin chains by forming a complex with HOIL-1L and SHARPIN in mammals. Here, we provide the first evidence of linear ubiquitination induced by a HOIP orthologue in Drosophila We identify Drosophila CG11321, which we named Linear Ubiquitin E3 ligase (LUBEL), and find that it catalyzes linear ubiquitination in vitro We detect endogenous linear ubiquitin chain-derived peptides by mass spectrometry in Drosophila Schneider 2 cells and adult flies. Furthermore, using CRISPR/Cas9 technology, we establish linear ubiquitination-defective flies by mutating residues essential for the catalytic activity of LUBEL Linear ubiquitination signals accumulate upon heat shock in flies...
October 4, 2016: EMBO Reports
Keshi Chen, Qi Long, Tao Wang, Danyun Zhao, Yanshuang Zhou, Juntao Qi, Yi Wu, Shengbiao Li, Chunlan Chen, Xiaoming Zeng, Jianguo Yang, Zisong Zhou, Weiwen Qin, Xiyin Liu, Yuxing Li, Yingying Li, Xiaofen Huang, Dajiang Qin, Jiekai Chen, Guangjin Pan, Hans R Schöler, Guoliang Xu, Xingguo Liu, Duanqing Pei
Reprogramming of somatic cells to induced pluripotent stem cells rewrites the code of cell fate at the chromatin level. Yet, little is known about this process physically. Here, we describe a fluorescence recovery after photobleaching method to assess the dynamics of heterochromatin/euchromatin and show significant heterochromatin loosening at the initial stage of reprogramming. We identify growth arrest and DNA damage-inducible protein a (Gadd45a) as a chromatin relaxer in mouse embryonic fibroblasts, which also enhances somatic cell reprogramming efficiency...
October 4, 2016: EMBO Reports
Marco M Candeias, Masatoshi Hagiwara, Michiyuki Matsuda
Wild-type p53 functions as a tumour suppressor while mutant p53 possesses oncogenic potential. Until now it remains unclear how a single mutation can transform p53 into a functionally distinct gene harbouring a new set of original cellular roles. Here we show that the most common p53 cancer mutants express a larger number and higher levels of shorter p53 protein isoforms that are translated from the mutated full-length p53 mRNA. Cells expressing mutant p53 exhibit "gain-of-function" cancer phenotypes, such as enhanced cell survival, proliferation, invasion and adhesion, altered mammary tissue architecture and invasive cell structures...
October 4, 2016: EMBO Reports
Satoru Torii, Tatsushi Yoshida, Satoko Arakawa, Shinya Honda, Akira Nakanishi, Shigeomi Shimizu
Autophagy is an evolutionary conserved process that degrades subcellular constituents. Unlike starvation-induced autophagy, the molecular mechanism of genotoxic stress-induced autophagy has not yet been fully elucidated. In this study, we analyze the molecular mechanism of genotoxic stress-induced autophagy and identify an essential role of dephosphorylation of the Unc51-like kinase 1 (Ulk1) at Ser(637), which is catalyzed by the protein phosphatase 1D magnesium-dependent delta isoform (PPM1D). We show that after exposure to genotoxic stress, PPM1D interacts with and dephosphorylates Ulk1 at Ser(637) in a p53-dependent manner...
September 26, 2016: EMBO Reports
Minxing Li, Francesca Cole, Dharm S Patel, Sarah M Misenko, Joonyoung Her, Amy Malhowski, Ali Alhamza, Haiyan Zheng, Richard Baer, Thomas Ludwig, Maria Jasin, André Nussenzweig, Lourdes Serrano, Samuel F Bunting
BRCA1 mutations strongly predispose affected individuals to breast and ovarian cancer, but the mechanism by which BRCA1 acts as a tumor suppressor is not fully understood. Homozygous deletion of exon 2 of the mouse Brca1 gene normally causes embryonic lethality, but we show that exon 2-deleted alleles of Brca1 are expressed as a mutant isoform that lacks the N-terminal RING domain. This "RING-less" BRCA1 protein is stable and efficiently recruited to the sites of DNA damage. Surprisingly, robust RAD51 foci form in cells expressing RING-less BRCA1 in response to DNA damage, but the cells nonetheless display the substantial genomic instability...
September 26, 2016: EMBO Reports
Massimo D'Agostino, Herre Jelger Risselada, Andreas Mayer
SNAREs fuse membranes in several steps. Trans-SNARE complexes juxtapose membranes, induce hemifused stalk structures, and open the fusion pore. A recent penetration model of fusion proposed that SNAREs force the hydrophilic C-termini of their transmembrane domains through the hydrophobic core of the membrane(s). In contrast, the indentation model suggests that the C-termini open the pore by locally compressing and deforming the stalk. Here we test these models in the context of yeast vacuole fusion. Addition of small hydrophilic tags renders bilayer penetration by the C-termini energetically unlikely...
September 19, 2016: EMBO Reports
Efrain M Ribot, Kelley B Hise
No abstract text is available yet for this article.
September 19, 2016: EMBO Reports
Annapurna Devi Allu, Yariv Brotman, Gang-Ping Xue, Salma Balazadeh
Responses to pathogens, including host transcriptional reprogramming, require partially antagonistic signalling pathways dependent on the phytohormones salicylic (SA) and jasmonic (JA) acids. However, upstream factors modulating the interplay of these pathways are not well characterized. Here, we identify the transcription factor ANAC032 from Arabidopsis thaliana as one such regulator in response to the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 (Pst). ANAC032 directly represses MYC2 activation upon Pst attack, resulting in blockage of coronatine-mediated stomatal reopening which restricts entry of bacteria into plant tissue...
September 15, 2016: EMBO Reports
Hernán R Bonomi, Laila Toum, Gabriela Sycz, Rodrigo Sieira, Andrés M Toscani, Gustavo E Gudesblat, Federico C Leskow, Fernando A Goldbaum, Adrián A Vojnov, Florencia Malamud
Phytochromes constitute a major photoreceptor family found in plants, algae, fungi, and prokaryotes, including pathogens. Here, we report that Xanthomonas campestris pv. campestris (Xcc), the causal agent of black rot disease which affects cruciferous crops worldwide, codes for a functional bacteriophytochrome (XccBphP). XccBphP possesses an N-terminal PAS2-GAF-PHY photosensory domain triad and a C-terminal PAS9 domain as its output module. Our results show that illumination of Xcc, prior to plant infection, attenuates its virulence in an XccBphP-dependent manner...
September 12, 2016: EMBO Reports
Alex A Compton, Nicolas Roy, Françoise Porrot, Anne Billet, Nicoletta Casartelli, Jacob S Yount, Chen Liang, Olivier Schwartz
The interferon-induced transmembrane (IFITM) proteins protect host cells from diverse virus infections. IFITM proteins also incorporate into HIV-1 virions and inhibit virus fusion and cell-to-cell spread, with IFITM3 showing the greatest potency. Here, we report that amino-terminal mutants of IFITM3 preventing ubiquitination and endocytosis are more abundantly incorporated into virions and exhibit enhanced inhibition of HIV-1 fusion. An analysis of primate genomes revealed that IFITM3 is the most ancient antiviral family member of the IFITM locus and has undergone a repeated duplication in independent host lineages...
September 6, 2016: EMBO Reports
Vijayalakshmi Kari, Wael Yassin Mansour, Sanjay Kumar Raul, Simon J Baumgart, Andreas Mund, Marian Grade, Hüseyin Sirma, Ronald Simon, Hans Will, Matthias Dobbelstein, Ekkehard Dikomey, Steven A Johnsen
The CHD1 gene, encoding the chromo-domain helicase DNA-binding protein-1, is one of the most frequently deleted genes in prostate cancer. Here, we examined the role of CHD1 in DNA double-strand break (DSB) repair in prostate cancer cells. We show that CHD1 is required for the recruitment of CtIP to chromatin and subsequent end resection during DNA DSB repair. Our data support a role for CHD1 in opening the chromatin around the DSB to facilitate the recruitment of homologous recombination (HR) proteins. Consequently, depletion of CHD1 specifically affects HR-mediated DNA repair but not non-homologous end joining...
September 5, 2016: EMBO Reports
Karolina Pakos-Zebrucka, Izabela Koryga, Katarzyna Mnich, Mila Ljujic, Afshin Samali, Adrienne M Gorman
In response to diverse stress stimuli, eukaryotic cells activate a common adaptive pathway, termed the integrated stress response (ISR), to restore cellular homeostasis. The core event in this pathway is the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) by one of four members of the eIF2α kinase family, which leads to a decrease in global protein synthesis and the induction of selected genes, including the transcription factor ATF4, that together promote cellular recovery. The gene expression program activated by the ISR optimizes the cellular response to stress and is dependent on the cellular context, as well as on the nature and intensity of the stress stimuli...
October 2016: EMBO Reports
Kathinka Evers, Jean-Pierre Changeux
No abstract text is available yet for this article.
October 2016: EMBO Reports
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