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FEBS Journal

Supriya V Vartak, Swarup H Ashok, Vidya Gopalakrishnan, K G Vindya, Virginie Ropars, Mridula Nambiar, Franklin John, S Sharath Kumar Kothanahally, Rupa Kumari, Nitu Kumari, Ujjayinee Ray, Gudapureddy Radha, Depina Dinesh, Monica Pandey, Ananda Hanumappa, Subhas S Karki, Mrinal Srivastava, Jean Baptiste Charbonnier, Bibha Choudhary, Kempegowda Mantelingu, Sathees C Raghavan
Nonhomologous DNA end joining (NHEJ) is the major DNA double-strand break (DSB) repair pathway in mammals. Previously, we have described a small molecule inhibitor, SCR7, which can inhibit NHEJ in a Ligase IV-dependent manner. Administration of SCR7 within the cells resulted in the accumulation of DNA breaks, cell death and inhibition of tumor growth in mice. In the present study, we report that parental SCR7, which is unstable can get autocyclized into a stable form. Both parental SCR7 and cyclized SCR7 possess the same molecular weight (334...
September 19, 2018: FEBS Journal
Mikkel Schultz-Johansen, Marie Cueff, Kévin Hardouin, Murielle Jam, Robert Larocque, Mikkel Andreas Glaring, Cécile Hervé, Mirjam Czjzek, Peter Stougaard
Sulfated fucans, often denoted fucoidans, are highly variable cell wall polysaccharides of brown algae, which possess a wide range of bioactive properties with potential pharmaceutical applications. Due to their complex architecture, the structures of algal fucans have until now only been partly determined. Enzymes capable of hydrolyzing sulfated fucans may allow specific release of defined bioactive oligosaccharides and may serve as a tool for structural elucidation of algal walls. Currently, such enzymes include only a few hydrolases belonging to the glycoside hydrolase family 107 (GH107), and little is known about their mechanistics and the substrates they degrade...
September 19, 2018: FEBS Journal
Pablo Baquero, Amy Dawson, G Vignir Helgason
Despite the development of selective BCR-ABL-targeting tyrosine kinase inhibitors (TKIs) transforming the management of chronic myeloid leukaemia (CML), therapy-resistant leukaemic stem cells (LSCs) persist after TKI treatment and present an obstacle to a CML cure. Recently, we and others have made significant contributions to the field by unravelling survival dependencies in LSCs to work towards the goal of eradicating LSCs in CML patients. In this review, we describe these findings focusing on autophagy and mitochondrial metabolism, which have recently been uncovered as two essential processes for LSCs quiescence and survival, respectively...
September 17, 2018: FEBS Journal
Susan Sammak, Mark D Allen, Najoua Hamdani, Mark Bycroft, Giovanna Zinzalla
c-MYC and the SWI/SNF chromatin remodeling complex act as master regulators of transcription, and play a key role in human cancer. Although they are known to interact, the molecular details of their interaction are lacking. We have determined the structure of the RPT1 region of the INI1/hSNF5/BAF47/SMARCB1 subunit of the SWI/SNF complex that acts as a c-MYC-binding domain, and have localized the interaction regions on both INI1 and on the c-MYC:MAX heterodimer. c-MYC interacts with a highly-conserved groove on INI1, while INI1 binds to the c-MYC Helix-Loop-Helix region...
September 17, 2018: FEBS Journal
Clara Marincowitz, Amanda Genis, Nandu Goswami, Patrick De Boever, Tim S Nawrot, Hans Strijdom
Mounting evidence points to increased rates of cardiovascular disease (CVD) among people living with HIV/AIDS (PLWHA). Endothelial dysfunction (loss of endothelium-dependent vascular relaxation in response to pro-vasodilatory stimuli) constitutes an early pathophysiological event in atherogenesis and CVD. Both HIV-1 infection and antiretroviral therapy (ART) are implicated in the development of endothelial dysfunction; however, conclusions are frequently drawn from associations shown in epidemiological studies...
September 16, 2018: FEBS Journal
Jakob Weiszmann, Lisa Fürtauer, Wolfram Weckwerth, Thomas Nägele
Stabilization of central carbohydrate metabolism plays a key role in plant stress response. Carbohydrates are substrate for numerous metabolic and stress-responsive reactions and have been shown to be involved in diverse signalling processes on a whole plant level. Regulation of enzymatic sucrose synthesis and degradation is well-known to be central to many stress-related processes as it significantly impacts stress tolerance. Leaf sucrose metabolism involves sucrose cleavage by invertases and ATP-consuming re-synthesis catalysed by hexokinase and sucrose phosphate synthase...
September 14, 2018: FEBS Journal
Sumana Roy, Sudeshna Das Chakraborty, Sampa Biswas
Human cathepsin K (CTSK) is a collagenolytic lysosomal cysteine protease that plays an important role in bone turnover. Mutation in CTSK gene is associated with loss of collagenolytic activity of CTSK leading to an autosomal recessive bone disorder called pycnodysostosis. Though a number of pycnodysostotic missense mutations have been reported, underlying mechanism of the disease is not clear. In this study we investigated in vitro six recombinant pycnodysostosis related mutants of human CTSK (G79E, I249T, G243E, G303E, G319C and Q187P)...
September 10, 2018: FEBS Journal
Hannah Almuttaqi, Irina A Udalova
Interferon regulatory factor 5 (IRF5) belongs to a family of transcription factors, originally implicated in anti-viral responses and interferon (IFN) production. However, studies conducted in different laboratories over the last decade have placed IRF5 as a central regulator of the inflammatory response. It has become clear that IRF5 contributes to the pathogenesis of many inflammatory and autoimmune diseases, such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE)...
September 10, 2018: FEBS Journal
Zobia Noreen, Chacko Jobichen, Rashda Abbasi, Jayaraman Seetharaman, J Sivaraman, Habib Bohkhari
The Type VI Secretion System (T6SS) provides enhanced virulence to Campylobacter jejuni and has been associated with a high incidence of bloody diarrhea. The hemolysin-coregulated protein (Hcp)-the hallmark of the T6SS-can act as a structural and effector protein. Unlike other T6SS-harboring bacteria, which possess multiple Hcp proteins each performing different functions, C. jejuni possesses only one Hcp protein, and its structural and functional role has not been elucidated previously. Here, we report the structure and functional studies of Hcp from C...
September 7, 2018: FEBS Journal
Xiaochun Wu, Zhi Chen, Yuan Gao, Lei Wang, Xiaofan Sun, Yaping Jin, Wei Liu
The krüppel like factors (KLFs) are a family of transcription factor proteins that regulate a wide range of biological processes. In an RNAi-based screening experiment, we identified Dar1, which is a KLF member in Drosophila, inhibited the proliferation of intestinal stem cells (ISCs). We found suppression of Dar1 activated ISC proliferation; as a consequence, the ISCs and the young differentiated cells were increased. On the other hand, overexpression of Dar1 inhibited ISC division and blocked the formation of ISC lineages...
September 6, 2018: FEBS Journal
Xiaojing Wang, Jia Li, Zhongcheng Yang, Li Wang, Lei Li, Wenqing Deng, Juan Zhou, Longfei Wang, Chengqi Xu, Qiuyun Chen, Qing K Wang
The phlda3 gene encodes a small, 127-amino acid protein with only a PH domain, and is involved in tumor suppression, proliferation of islet β-cells, insulin secretion, glucose tolerance, and liver injury. However, the role of phlda3 in vascular development is unknown. Here, we show that phlda3 overexpression decreases the expression levels of hemangioblast markers scl, fli1, and etsrp and intersegmental vessel (ISV) markers flk1 and cdh5, and disrupts ISV development in tg(flk1:GFP) and tg(fli1:GFP) zebrafish...
September 6, 2018: FEBS Journal
Rafael A Paiva, Camila V Ramos, Vera C Martins
Cell competition in the thymus promotes turnover and functions as a tumor suppressor by inhibiting leukemia. Using thymus transplantation experiments, we have shown that the presence of T lymphocyte precursors, recently seeding the thymus, promotes the clearance of precursors with a longer time of thymus residency. If cell competition is impaired and no cells seed the thymus, the organ is capable of sustaining T lymphocyte production, a state termed thymus autonomy. However, we observed consistently that prolonged autonomy is permissive to the emergence of T cell acute lymphoblastic leukemia (T-ALL)...
September 5, 2018: FEBS Journal
Giedrius Sasnauskas, Elena Manakova, Kęstutis Lapėnas, Kotryna Kauneckaitė, Virginijus Siksnys
B3 transcription factors constitute a large plant-specific protein superfamily, which plays a central role in plant life. Family members are characterized by the presence of B3 DNA binding domains (DBDs). To date, only a few B3 DBDs were structurally characterized, therefore the DNA recognition mechanism of other family members remains to be elucidated. Here we analyze DNA recognition mechanism of two structurally uncharacterized B3 transcription factors, ABI3 and NGA1. Guided by the structure of the DNA-bound B3 domain of Arabidopsis transcriptional repressor VAL1, we have performed mutational analysis of the ABI3 B3 domain...
September 5, 2018: FEBS Journal
Edmundo Gassias, Nicolas Durand, Elodie Demondion, Thomas Bourgeois, Françoise Bozzolan, Stéphane Debernard
In the male moth, Agrotis ipsilon, the behavioural response and neuron sensitivity within the olfactory centres, the antennal lobes (ALs), to female sex pheromone increase with age, in correlation with the maturation of sex accessory glands (SAGs). By contrast, newly mated males cease to be attracted to sex pheromone and re-mate when their SAGs are refilled during the next night. The insect hormone receptor 38 (HR38), an ortholog of the vertebrate NR4A receptors, is a component of ecdysteroid signaling pathway which controls adult male physiology and behavior...
September 4, 2018: FEBS Journal
David Fiebig, Juliana Storka, Markus Roeder, Christian Meyners, Stefan Schmelz, Wulf Blankenfeldt, Andrea Scrima, Harald Kolmar, Hans-Lothar Fuchsbauer
The Dispase autolysis-inducing protein (DAIP) is produced by Streptomyces mobaraensis to disarm neutral metalloproteases by decomposition. Absence of a catalytic protease domain led to the assumption that the seven-bladed β-propeller protein DAIP causes structural modifications, thereby triggering autolysis. Determination of protein complexes consisting of DAIP and thermolysin or DAIP and a non-functional E138A bacillolysin variant supported this postulation. Protein twisting was indicated by DAIP-mediated inhibition of thermolysin while bacillolysin underwent immediate autolysis under the same conditions...
August 31, 2018: FEBS Journal
Philippe Marbet, Petra Klusonova, Julia Birk, Denise V Kratschmar, Alex Odermatt
Hexose-6-phosphate dehydrogenase (H6PD) is thought to be the major source of NADPH within the endoplasmic reticulum (ER), determining 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) reaction direction to convert inert 11-oxo- to potent 11β-hydroxyglucocorticoids. Here, we tested the hypothesis whether H6pd knock-out (KO) in primary murine bone marrow-derived macrophages results in a switch from 11β-HSD1 oxoreduction to dehydrogenation, thereby inactivating glucocorticoids (GC) and affecting macrophage phenotypic activation as well as causing a more aggressive M1 macrophage phenotype...
August 28, 2018: FEBS Journal
Bjarte Aarmo Lund, Ane Molden Thomassen, Birgit Helene Berg Nesheim, Trine Josefine Olsen Carlsen, Johan Isaksson, Tony Christopeit, Hanna-Kirsti S Leiros
Many class D β-lactamases form dimers in solution. The functional basis of the dimerization of OXA-48-like class D β-lactamases is not known, but in order to understand the structural requirements for dimerization of OXA-48, we have characterized the dimer interface. Size exclusion chromatography, small angle X-ray scattering (SAXS), and nuclear magnetic resonance (NMR) were used to confirm the oligomeric state of OXA-48 in solution. X-ray crystallographic structures were used to elucidate the key interactions of dimerization...
August 28, 2018: FEBS Journal
Víctor M Ayala-García, Noe Baruch-Torres, Paola L García-Medel, Luis G Brieba
The coding sequences of plant mitochondrial and chloroplast genomes present a lower mutation rate than the coding sequences of animal mitochondria. However, plant mitochondrial genomes frequently rearrange and present high mutation rates in their noncoding sequences. DNA replication in plant organelles is carried out by two DNA polymerases (DNAP) paralogs. In Arabidopsis thaliana at least one DNAP paralog (AtPolIA or AtPolIB) is necessary for plant viability, suggesting that both genes are partially redundant...
August 27, 2018: FEBS Journal
Wai Yan Yau, Emer O'Connor, Roisin Sullivan, Layan Akijian, Nicholas W Wood
The inherited cerebellar ataxias comprise of a genetic heterogeneous group of disorders. Pathogenic expansions of cytosine-adenine-guanine (CAG) encoding polyglutamine tracts account for the largest proportion of autosomal dominant cerebellar ataxias, while GAA expansion in the first introns of frataxin gene is the commonest cause of autosomal recessive cerebellar ataxias. Currently, there is no available treatment to alter the disease trajectory, with devastating consequences for affected individuals. Inter- and Intrafamily phenotypic variability suggest the existence of genetic modifiers, which may become targets amendable to treatment...
August 27, 2018: FEBS Journal
Madhulika Mishra, Priyanka Jayal, Anjali A Karande, Nagasuma Chandra
Sorafenib (SFB), a multi-kinase inhibitor, is the only approved drug for treating hepatocellular carcinoma (HCC). However, SFB shows low efficacy in many cases. HCC related mortality therefore remains to be high worldwide. SFB, a multi-kinase inhibitor is also known to modulate the redox homeostasis in cancer cells. To understand the effect of SFB on the redox status, a quantitative understanding of the system is necessary. Kinetic modeling of the relevant pathways is a useful approach for obtaining a quantitative understanding of the pathway dynamics and to rank the individual factors based on the extent of influence they wield on the pathway...
August 22, 2018: FEBS Journal
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