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Site directed mutations

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https://www.readbyqxmd.com/read/28212569/mir-124-acts-as-a-tumor-suppressor-by-inhibiting-the-expression-of-sphingosine-kinase-1-and-its-downstream-signaling-in-head-and-neck-squamous-cell-carcinoma
#1
Yuan Zhao, Zhiqiang Ling, Yubin Hao, Xiaowu Pang, Xianlin Han, Joseph A Califano, Liang Shan, Xinbin Gu
By analyzing the expression profile of microRNAs in head and neck squamous cell carcinomas (HNSCC), we found that the expression level of miR-124 was 4.59-fold lower in tumors than in normal tissues. To understand its functions, we generated a miR-124-expressing subline (JHU-22miR124) and a mock vector-transfected subline (JHU-22vec) by transfecting the mimic of miR-124 into JHU-22 cancer cells. Restored expression of miR-124 in JHU-22miR124 cells led to reduced cell proliferation, delayed colony formation, and decreased tumor growth, indicating a tumor-suppressive effect of miR-124...
February 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28212413/scarless-deletion-of-up-to-seven-methyl-accepting-chemotaxis-genes-with-an-optimized-method-highlights-key-function-of-chem-in-salmonella-typhimurium
#2
Stefanie Hoffmann, Christiane Schmidt, Steffi Walter, Jennifer K Bender, Roman G Gerlach
Site-directed scarless mutagenesis is an essential tool of modern pathogenesis research. We describe an optimized two-step protocol for genome editing in Salmonella enterica serovar Typhimurium to enable multiple sequential mutagenesis steps in a single strain. The system is based on the λ Red recombinase-catalyzed integration of a selectable antibiotics resistance marker followed by replacement of this cassette. Markerless mutants are selected by expressing the meganuclease I-SceI which induces double-strand breaks in bacteria still harboring the resistance locus...
2017: PloS One
https://www.readbyqxmd.com/read/28208862/correlation-of-p53-overexpression-with-the-clinicopathological-prognostic-factors-in-colorectal-adenocarcinoma
#3
Akshatha C, Vijaya Mysorekar, Arundhathi S, Arul P, Adithi Raj, Smitha Shetty
INTRODUCTION: Mutation in p53 gene and accumulation of p53 protein is a common genetic event in colorectal carcinomas. p53 mutation can be detected by various techniques such as DNA sequencing, polymerase chain reaction and immunohistochemistry (IHC). However, IHC is simple and is consistent with other techniques. AIM: To establish a correlation between overexpression of p53 with the clinical features, tumour histopathology and stage of Colorectal Carcinoma (CRC)...
December 2016: Journal of Clinical and Diagnostic Research: JCDR
https://www.readbyqxmd.com/read/28206745/atomistic-molecular-dynamics-simulations-of-mitochondrial-dna-polymerase-gamma-novel-mechanisms-of-function-and-pathogenesis
#4
Liliya Euro, Outi Haapanen, Tomasz Rog, Ilpo Vattulainen, Anu Suomalainen, Vivek Sharma
DNA polymerase gamma (Pol γ) is a key component of the mitochondrial DNA replisome and an important cause of neurological diseases. Despite the availability of its crystal structures, the molecular mechanism of DNA replication, the switch between polymerase and exonuclease activities, the site of replisomal interactions and functional effects of patient mutations that do not affect direct catalysis have remained elusive. Here we report first atomistic classical molecular dynamics (MD) simulations of human Pol γ replicative complex...
February 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/28204960/sites-and-functional-consequence-of-alkylphenol-anesthetic-binding-to-kv1-2-channels
#5
Weiming Bu, Qiansheng Liang, Lianteng Zhi, Lina Maciunas, Patrick J Loll, Roderic G Eckenhoff, Manuel Covarrubias
Inhalational general anesthetics, such as sevoflurane and isoflurane, modulate a subset of brain Kv1 potassium channels. However, the Kv1.2 channel is resistant to propofol, a commonly used intravenous alkylphenol anesthetic. We hypothesize that propofol binds to a presumed pocket involving the channel's S4-S5 linker, but functional transduction is poor and, therefore, propofol efficacy is low. To test this hypothesis, we used a photoactive propofol analog (meta-aziPropofol = AziPm) to directly probe binding and electrophysiological and mutational analyses in Xenopus oocytes to probe function...
February 15, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28199340/crystal-structure-and-structure-based-mutagenesis-of-actin-specific-adp-ribosylating-toxin-cpile-a-as-novel-enterotoxin
#6
Waraphan Toniti, Toru Yoshida, Toshiharu Tsurumura, Daisuke Irikura, Chie Monma, Yoichi Kamata, Hideaki Tsuge
Unusual outbreaks of food poisoning in Japan were reported in which Clostridium perfringens was strongly suspected to be the cause based on epidemiological information and fingerprinting of isolates. The isolated strains lack the typical C. perfringens enterotoxin (CPE) but secrete a new enterotoxin consisting of two components: C. perfringens iota-like enterotoxin-a (CPILE-a), which acts as an enzymatic ADP-ribosyltransferase, and CPILE-b, a membrane binding component. Here we present the crystal structures of apo-CPILE-a, NAD+-CPILE-a and NADH-CPILE-a...
2017: PloS One
https://www.readbyqxmd.com/read/28199309/phosphatidylinositol-3-kinase-%C3%AE-blockade-increases-genomic-instability-in-b-cells
#7
Mara Compagno, Qi Wang, Chiara Pighi, Taek-Chin Cheong, Fei-Long Meng, Teresa Poggio, Leng-Siew Yeap, Elif Karaca, Rafael B Blasco, Fernanda Langellotto, Chiara Ambrogio, Claudia Voena, Adrian Wiestner, Siddha N Kasar, Jennifer R Brown, Jing Sun, Catherine J Wu, Monica Gostissa, Frederick W Alt, Roberto Chiarle
Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation...
February 15, 2017: Nature
https://www.readbyqxmd.com/read/28199212/transposon-mediated-directed-mutation-in-bacteria-and-eukaryotes
#8
Milton H Saier, Chika Kukita, Zhongge Zhang
Transposon-mediated "directed" mutations occur at higher frequencies when beneficial than when detrimental and relieve the stress that causes them. The first and best-studied example involves regulation of Insertion Sequence-5 (IS5) insertion into a specific activating site upstream of the glycerol utilization operon in Escherichia coli, glpFK. This event promotes high level expression of the glpFK operon, allowing glycerol utilization in wild type cells under inhibitory conditions. The phosphoenolpyruvate-dependent, sugar transporting, phosphotransferase system (PTS) influences this process by regulating cytoplasmic glycerol-3-phosphate and cyclic AMP concentrations...
March 1, 2017: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28197171/genome-wide-microrna-binding-site-variation-between-extinct-wild-aurochs-and-modern-cattle-identifies-candidate-microrna-regulated-domestication-genes
#9
Martin Braud, David A Magee, Stephen D E Park, Tad S Sonstegard, Sinead M Waters, David E MacHugh, Charles Spillane
The domestication of cattle from the now-extinct wild aurochs (Bos primigenius) involved selection for physiological and behavioral traits, with underlying genetic factors that remain largely unknown. Non-coding microRNAs have emerged as key regulators of the spatio-temporal expression of target genes controlling mammalian growth and development, including in livestock species. During the domestication process, selection of mutational changes in miRNAs and/or miRNA binding sites could have provided a mechanism to generate some of the traits that differentiate domesticated cattle from wild aurochs...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/28196451/phenotypic-and-genetic-analysis-of-dysprothrombinemia-due-to-a-novel-homozygous-mutation
#10
Kankan Su, Yanhui Jin, Zhihai Miao, Xiaoli Cheng, Lihong Yang, Mingshan Wang
OBJECTIVE: We study the phenotype and genotype of a novel gene mutation of factor II (FII) that leads to dysprothrombinemia, and do the meta-analysis to illuminate its molecular pathogenesis. It will further contribute to our comprehension of the pathogenesis of this type of disease. METHODS: The prothrombin time (PT), activated partial thromboplastin time (APTT) and the activities of other factors were determined by the one-stage clotting method. The prothrombin antigen was measured with enzyme-linked immunosorbent assay (ELISA)...
February 14, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28195196/arabidopsis-thaliana-dehydroascorbate-reductase-2-conformational-flexibility-during-catalysis
#11
Nandita Bodra, David Young, Leonardo Astolfi Rosado, Anna Pallo, Khadija Wahni, Frank De Proft, Jingjing Huang, Frank Van Breusegem, Joris Messens
Dehydroascorbate reductase (DHAR) catalyzes the glutathione (GSH)-dependent reduction of dehydroascorbate and plays a direct role in regenerating ascorbic acid, an essential plant antioxidant vital for defense against oxidative stress. DHAR enzymes bear close structural homology to the glutathione transferase (GST) superfamily of enzymes and contain the same active site motif, but most GSTs do not exhibit DHAR activity. The presence of a cysteine at the active site is essential for the catalytic functioning of DHAR, as mutation of this cysteine abolishes the activity...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28193843/bound-substrate-in-the-structure-of-cyanobacterial-branching-enzyme-supports-a-new-mechanistic-model
#12
Mari Hayashi, Ryuichiro Suzuki, Christophe Colleoni, Steven G Ball, Naoko Fujita, Eiji Suzuki
Branching enzyme (BE) catalyzes the formation of α-1,6-glucosidic linkages in amylopectin and glycogen. The reaction products are variable depending on the organism sources, and the mechanistic basis for these different outcomes is unclear. Although most cyanobacteria have only one BE isoform belonging to glycoside hydrolase (GH) family 13, Cyanothece sp. ATCC 51142 has three isoforms (BE1, BE2, and BE3) with distinct enzymatic properties, suggesting that investigations of these enzymes might provide unique insights into this system...
February 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28193728/mobile-introns-shape-the-genetic-diversity-of-their-host-genes
#13
Jelena Repar, Tobias Warnecke
Self-splicing introns populate several highly conserved protein-coding genes in fungal and plant mitochondria. In fungi, many of these introns have retained their ability to spread to intron-free target sites, often assisted by intron-encoded endonucleases that initiate the homing process. Here, leveraging population genomic data from Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Lachancea kluyveri, we expose non-random patterns of genetic diversity in exons that border self-splicing introns. In particular, we show that, in all three species, the density of single nucleotide polymorphisms increases as one approaches a mobile intron...
February 13, 2017: Genetics
https://www.readbyqxmd.com/read/28192668/key-role-of-the-carboxyl-terminus-of-hyaluronan-synthase-in-processive-synthesis-and-size-control-of-hyaluronic-acid-polymers
#14
Ji Yang, Fangyu Cheng, Huimin Yu, Junting Wang, Guo Zhi Gang, Gregory Stephanopoulos
The essential pathophysiological roles of hyaluronic acid (HA) strongly depend on HA binding and HA size. Here we deployed the atomic vision of molecular dynamics (MD) simulation to experimentally investigate the influence of C-terminal mutations of Streptococcus equisimilis hyaluronan synthase (SeHAS) on HA product synthesis in Escherichia coli. R413 was vital for HA production, as the removal or mutation of R413 led to inactivation of SeHAS. MD simulations indicated that R406-R413 constituted an HA-binding pattern that stabilized the HA-SeHAS complex...
February 13, 2017: Biomacromolecules
https://www.readbyqxmd.com/read/28188228/time-resolved-phosphoproteome-analysis-of-paradoxical-raf-activation-reveals-novel-targets-of-erk
#15
Peter Kubiniok, Hugo Lavoie, Marc Therrien, Pierre Thibault
Small molecules targeting aberrant RAF activity, like Vemurafenib (PLX4032), are highly effective against cancers harboring the V600E BRAF mutation, and are now approved for clinical use against metastatic melanoma. However, in tissues showing elevated RAS activity and in RAS-mutant tumors, these inhibitors stimulate RAF dimerization, resulting in inhibitor resistance and downstream paradoxical ERK activation. To understand the global signaling response of cancer cells to RAF inhibitors, we profiled the temporal changes of the phosphoproteome of two colon cancer cell lines (Colo205 and HCT116) that respond differently to Vemurafenib...
February 10, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28182633/characterizing-the-coding-region-determinant-binding-protein-crd-bp-microphthalmia-associated-transcription-factor-mitf-mrna-interaction
#16
Gerrit van Rensburg, Sebastian Mackedenski, Chow H Lee
Coding region determinant-binding protein (CRD-BP) binds to the 3'-UTR of microphthalmia-associated transcription factor (MITF) mRNA to prevent its targeted degradation by miR-340. Here, we aim to further understand the molecular interaction between CRD-BP and MITF RNA. Using point mutation in the GXXG motif of each KH domains, we showed that all four KH domains of CRD-BP are important for their physical association with MITF RNA. We mapped the CRD-BP-binding site in the 3'-UTR of MITF RNA from nts 1330-1740 and showed that the 49-nt fragment 1621-1669 is the minimal size MITF RNA for binding...
2017: PloS One
https://www.readbyqxmd.com/read/28182326/ghmyb1-regulates-scw-stage-specific-expression-of-the-ghgdsl-promoter-in-the-fibers-of-gossypium-hirsutum-l
#17
Vrijesh Kumar Yadav, Vikash Kumar Yadav, Poonam Pant, Surendra Pratap Singh, Rashmi Maurya, Anshulika Sable, Samir V Sawant
Secondary cell wall (SCW) biosynthesis is an important stage of the cotton fiber development, its transcriptional regulation is poorly understood. We selected the Gossypium hirsutum GDSL (GhGDSL) lipase/hydrolase gene (CotAD_74480), which is expressed during SCW biosynthesis (19 through to 25 Days Post Anthesis; DPA), for study. T1 -transgenic cotton lines expressing the β-glucuronidase (gus) reporter under the control of a 1026-bp promoter fragment of GhGDSL (PGhGDSL ) showed 19 DPA stage-specific increase in GUS expression...
February 9, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/28179528/identification-of-novel-functions-for-hepatitis-c-virus-envelope-glycoprotein-e1-in-virus-entry-and-assembly
#18
Juliano Haddad, Yves Rouillé, Xavier Hanoulle, Véronique Descamps, Monzer Hamze, Fouad Dabboussi, Thomas F Baumert, Gilles Duverlie, Muriel Lavie, Jean Dubuisson
Hepatitis C Virus (HCV) envelope glycoprotein complex is composed of E1 and E2 subunits. E2 is the receptor-binding protein as well as the major target of neutralizing antibodies, whereas the functions of E1 remain poorly defined. Here, we took advantage of the recently published structure of the N-terminal region of E1 ectodomain to interrogate the functions of this glycoprotein by mutating residues within this 79 amino acid region in the context of an infectious clone. The phenotypes of the mutants were characterized to determine the effects of the mutations on virus entry, replication and assembly...
February 8, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28174298/the-startle-disease-mutation-e103k-impairs-activation-of-human-homomeric-%C3%AE-1-glycine-receptors-by-disrupting-an-intersubunit-salt-bridge-across-the-agonist-binding-site
#19
Fatemah Safar, Elliot Hurdiss, Marios Erotocritou, Timo Greiner, Remigijus Lape, Mark W Irvine, Guangyu Fang, David Jane, Rilei Yu, Marc A Dämgen, Philip C Biggin, Lucia G Sivilotti
Glycine receptors (GlyR) belong to the pentameric ligand gated ion channel (pLGIC) superfamily and mediate fast inhibitory transmission in the vertebrate CNS. Disruption of glycinergic transmission by inherited mutations produces startle disease in man. Many startle mutations are in GlyRs and provide useful clues to the function of the channel domains. E103K is one of few startle mutations found in the extracellular agonist binding site of the channel, in loop A of the principal side of the subunit interface...
February 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28173748/susceptibility-to-type-2-diabetes-may-be-modulated-by-haplotypes-in-g6pc2-a-target-of-positive-selection
#20
Nasser M Al-Daghri, Chiara Pontremoli, Rachele Cagliani, Diego Forni, Majed S Alokail, Omar S Al-Attas, Shaun Sabico, Stefania Riva, Mario Clerici, Manuela Sironi
BACKGROUND: The endoplasmic reticulum enzyme glucose-6-phosphatase catalyzes the common terminal reaction in the gluconeogenic/glycogenolytic pathways and plays a central role in glucose homeostasis. In most mammals, different G6PC subunits are encoded by three paralogous genes (G6PC, G6PC2, and G6PC3). Mutations in G6PC and G6PC3 are responsible for human mendelian diseases, whereas variants in G6PC2 are associated with fasting glucose (FG) levels. RESULTS: We analyzed the evolutionary history of G6Pase genes...
February 7, 2017: BMC Evolutionary Biology
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