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Ribonucleotide reductase

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https://www.readbyqxmd.com/read/28928213/cell-cycle-inhibition-to-treat-sleeping-sickness
#1
Conrad L Epting, Brian T Emmer, Nga Y Du, Joann M Taylor, Ming Y Makanji, Cheryl L Olson, David M Engman
African trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Like all eukaryotes, T. brucei has a cell cycle involving the de novo synthesis of DNA regulated by ribonucleotide reductase (RNR), which catalyzes the conversion of ribonucleotides into their deoxy form. As an essential enzyme for the cell cycle, RNR is a common target for cancer chemotherapy...
September 19, 2017: MBio
https://www.readbyqxmd.com/read/28927142/tumour-growth-suppressive-effect-of-arsenic-trioxide-in-squamous-cell-lung-carcinoma
#2
Leanne Lee Leung, Sze-Kwan Lam, Yuan-Yuan Li, James Chung-Man Ho
Lung squamous cell carcinoma (SCC) is the second most common subtype of non-small cell lung carcinoma. The anticancer effects of arsenic trioxide (ATO) in lung adenocarcinoma and small-cell lung cancer have previously been reported; however its effects in SCC remain unclear. An MTT assay and western blot analysis were performed to determine cell viability and protein expression, respectively, in the SK-MES-1 and SW900 SCC cell lines following treatment with ATO. Phosphatidylserine externalization, mitochondrial membrane depolarization and cell cycle distribution were studied using flow cytometry and the in vivo effects of ATO on tumour growth were investigated with a xenograft model...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28903048/set2-methyltransferase-facilitates-dna-replication-and-promotes-genotoxic-stress-responses-through-mbf-dependent-transcription
#3
Chen-Chun Pai, Anastasiya Kishkevich, Rachel S Deegan, Andrea Keszthelyi, Lisa Folkes, Stephen E Kearsey, Nagore De León, Ignacio Soriano, Robertus Antonius Maria de Bruin, Antony M Carr, Timothy C Humphrey
Chromatin modification through histone H3 lysine 36 methylation by the SETD2 tumor suppressor plays a key role in maintaining genome stability. Here, we describe a role for Set2-dependent H3K36 methylation in facilitating DNA replication and the transcriptional responses to both replication stress and DNA damage through promoting MluI cell-cycle box (MCB) binding factor (MBF)-complex-dependent transcription in fission yeast. Set2 loss leads to reduced MBF-dependent ribonucleotide reductase (RNR) expression, reduced deoxyribonucleoside triphosphate (dNTP) synthesis, altered replication origin firing, and a checkpoint-dependent S-phase delay...
September 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/28887583/mir-608-regulating-the-expression-of-ribonucleotide-reductase-m1-and-cytidine-deaminase-is-repressed-through-induced-gemcitabine-chemoresistance-in-pancreatic-cancer-cells
#4
Azam Rajabpour, Ali Afgar, Habibollah Mahmoodzadeh, Jalal-E-Din Radfar, Farzad Rajaei, Ladan Teimoori-Toolabi
PURPOSE: Gemcitabine resistance is the main problem in pancreatic adenocarcinoma patients. Hence, we aimed to identify the correlation between expression of RRM1 and CDA as the resistance genes and their predicted targeting miR-608 in the resistant pancreatic cancer cell lines to gemcitabine. METHODS: Dual luciferase assay was performed to determine whether both RRM1 and CDA are targeted by miR-608 in 293T and pancreatic cancer cell lines. AsPC-1 and MIA PaCa-2 cell lines became gradually resistant to gemcitabine by exposing to the increasing doses of gemcitabine...
September 8, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28881312/lc-ms-ms-assay-for-the-quantitation-of-the-ribonucleotide-reductase-inhibitor-triapine-in-human-plasma
#5
Julia Matsumoto, Brian F Kiesel, Robert A Parise, Jianxia Guo, Sarah Taylor, Marilyn Huang, Julie L Eiseman, S Percy Ivy, Charles Kunos, Edward Chu, Jan H Beumer
The ribonucleotide reductase inhibitor and radiosensitizer triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP), NSC 663249) is clinically being evaluated via the intravenous (IV) route for the treatment of cervical and vulvar cancer in combination with primary cisplatin chemoradiation. The need for a 2-h infusion and frequent administration of triapine is logistically challenging, prompting us to pursue oral (PO) administration. In support of the clinical trial investigating oral triapine in combination with chemoradiation, we developed and validated a novel LC-MS/MS assay for the quantification of triapine in 50μL human plasma...
August 31, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28879348/the-elemental-role-of-iron-in-dna-synthesis-and-repair
#6
REVIEW
Sergi Puig, Lucía Ramos-Alonso, Antonia María Romero, María Teresa Martínez-Pastor
Iron is an essential redox element that functions as a cofactor in many metabolic pathways. Critical enzymes in DNA metabolism, including multiple DNA repair enzymes (helicases, nucleases, glycosylases, demethylases) and ribonucleotide reductase, use iron as an indispensable cofactor to function. Recent striking results have revealed that the catalytic subunit of DNA polymerases also contains conserved cysteine-rich motifs that bind iron-sulfur (Fe/S) clusters that are essential for the formation of stable and active complexes...
September 7, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28878380/an-in-silico-approach-to-predict-and-exploit-synthetic-lethality-in-cancer-metabolism
#7
Iñigo Apaolaza, Edurne San José-Eneriz, Luis Tobalina, Estíbaliz Miranda, Leire Garate, Xabier Agirre, Felipe Prósper, Francisco J Planes
Synthetic lethality is a promising concept in cancer research, potentially opening new possibilities for the development of more effective and selective treatments. Here, we present a computational method to predict and exploit synthetic lethality in cancer metabolism. Our approach relies on the concept of genetic minimal cut sets and gene expression data, demonstrating a superior performance to previous approaches predicting metabolic vulnerabilities in cancer. Our genetic minimal cut set computational framework is applied to evaluate the lethality of ribonucleotide reductase catalytic subunit M1 (RRM1) inhibition in multiple myeloma...
September 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28872846/tuning-the-diiron-core-geometry-in-carboxylate-bridged-macrocyclic-model-complexes-affects-their-redox-properties-and-supports-oxidation-chemistry
#8
Fang Wang, Sabine Becker, Mikael A Minier, Andrei Loas, Megan N Jackson, Stephen J Lippard
We introduce a novel platform to mimic the coordination environment of carboxylate-bridged diiron proteins by tethering a small, dangling internal carboxylate, (CH2)nCOOH, to phenol-imine macrocyclic ligands (H3PIMICn). In the presence of an external bulky carboxylic acid (RCO2H), the ligands react with [Fe2(Mes)4] (Mes = 2,4,6-trimethylphenyl) to afford dinuclear [Fe2(PIMICn)(RCO2)(MeCN)] (n = 4-6) complexes. X-ray diffraction studies revealed structural similarities between these complexes and the reduced diiron active sites of proteins such as Class I ribonucleotide reductase (RNR) R2 and soluble methane monooxygenase hydroxylase...
September 5, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28841361/p53r2-overexpression-in-cervical-cancer-promotes-akt-signaling-and-emt-and-is-correlated-with-tumor-progression-metastasis-and-poor-prognosis
#9
Chao Jiang, Rui Xu, Xiao-Xing Li, Yan-Yan Wang, Wen-Qian Liang, Ju-Deng Zeng, Shan-Shan Zhang, Xiao-Yi Xu, Yang Yang, Mei-Yin Zhang, Hui-Yun Wang, X F Steven Zheng
p53R2 is a p53-inducible ribonucleotide reductase subunit involved in deoxyribonucleotide biosynthesis and DNA repair. Although p53R2 has been linked to human cancer, its role in cervical cancer remains unknown. In this study, we investigated the expression and clinical significance of p53R2 in early-stage cervical cancer. p53R2 expression is significantly upregulated at both mRNA and protein levels in cervical cancer cells and tissues, compared with that in matched normal cervical cells and tissues, respectively...
September 17, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28837865/valproic-acid-sensitizes-breast-cancer-cells-to-hydroxyurea-through-inhibiting-rpa2-hyperphosphorylation-mediated-dna-repair-pathway
#10
Youjia Tian, Guochao Liu, Hui Wang, Zhujun Tian, Zuchao Cai, Fengmei Zhang, Yue Luo, Shue Wang, Gongshe Guo, Xiaowei Wang, Simon Powell, Zhihui Feng
It was reported that valproic acid (VPA, a histone deacetylase inhibitor) can sensitize cancer cells to hydroxyurea (HU, a ribonucleotide reductase inhibitor) for chemotherapy, although the mechanism of VPA-induced HU sensitization is unclear. In this study, we systematically characterized VPA-induced HU sensitization of breast cancer cells. Multiple breast cancer cell models were employed to investigate whether the safe concentration of 0.5mM VPA and 2mM HU can result in DNA double-strand breaks (DSBs) and impact cell survival...
August 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28836557/-18-f-fluorodeoxyglucose-uptake-with-expression-of-excision-repair-cross-complementary-group-1-and-ribonucleotide-reductase-subunit-m1-in-non-small-cell-lung-cancer
#11
Na Hu, Yun-Hua Wang, Dai-Qiang Li, Xiao-Huang Yang, Yan-Lin Tan
No abstract text is available yet for this article.
September 5, 2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/28808226/atr-inhibition-facilitates-targeting-of-leukemia-dependence-on-convergent-nucleotide-biosynthetic-pathways
#12
Thuc M Le, Soumya Poddar, Joseph R Capri, Evan R Abt, Woosuk Kim, Liu Wei, Nhu T Uong, Chloe M Cheng, Daniel Braas, Mina Nikanjam, Peter Rix, Daria Merkurjev, Jesse Zaretsky, Harley I Kornblum, Antoni Ribas, Harvey R Herschman, Julian Whitelegge, Kym F Faull, Timothy R Donahue, Johannes Czernin, Caius G Radu
Leukemia cells rely on two nucleotide biosynthetic pathways, de novo and salvage, to produce dNTPs for DNA replication. Here, using metabolomic, proteomic, and phosphoproteomic approaches, we show that inhibition of the replication stress sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) reduces the output of both de novo and salvage pathways by regulating the activity of their respective rate-limiting enzymes, ribonucleotide reductase (RNR) and deoxycytidine kinase (dCK), via distinct molecular mechanisms...
August 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/28808063/phylogenetic-sequence-analysis-and-functional-studies-reveal-compensatory-amino-acid-substitutions-in-loop-2-of-human-ribonucleotide-reductase
#13
Andrew J Knappenberger, Sneha Grandhi, Reena Sheth, Md Faiz Ahmad, Rajesh Viswanathan, Michael E Harris
Eukaryotic class I ribonucleotide reductases (RRs) generate deoxyribonucleotides for DNA synthesis. Binding of dNTP effectors is coupled to the formation of active dimers and induces conformational changes in a short loop (loop 2) to regulate RR's specificity among its nucleoside diphosphate (NDP) substrates. Moreover, ATP and dATP bind at an additional allosteric site 40 Å away from loop 2 and thereby drive formation of activated or inactive hexamers, respectively. To better understand how dNTP binding influences specificity, activity, and oligomerization of human RR, we aligned >300 eukaryotic RR sequences to examine natural sequence variation in loop 2...
August 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28797284/gambogic-acid-sensitizes-gemcitabine-efficacy-in-pancreatic-cancer-by-reducing-the-expression-of-ribonucleotide-reductase-subunit-m2-rrm2
#14
Guanggai Xia, Hongcheng Wang, Ziliang Song, Qingcai Meng, Xiuyan Huang, Xinyu Huang
BACKGROUND: Pancreatic cancer is susceptible to gemcitabine resistance, and patients receive less benefit from gemcitabine chemotherapy. Previous studies report that gambogic acid possesses antineoplastic properties; however, to our knowledge, there have been no specific studies on its effects in pancreatic cancer. Therefore, the purpose of this study was to explore whether increases the sensitivity of pancreatic cancer to gemcitabine, and determine the synergistic effects of gambogic acid and gemcitabine against pancreatic cancer...
August 10, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28778071/suppression-of-pancreatic-adenocarcinoma-upregulated-factor-pauf-increases-the-sensitivity-of-pancreatic-cancer-to-gemcitabine-and-5fu-and-inhibits-the-formation-of-pancreatic-cancer-stem-like-cells
#15
Jae Hee Cho, Sun A Kim, Soo Been Park, Hee Man Kim, Si Young Song
Pancreatic cancer stem cells (CSCs) play a crucial role in tumorigenesis and chemoresistance of pancreatic ductal adenocarcinoma. Pancreatic adenocarcinoma up-regulated factor (PAUF), a novel secretory protein, has been shown to contribute to cancer progression and metastasis. Because the clinical relationship between PAUF and pancreatic CSCs is largely unknown, we investigated the associations between the functional role of PAUF and pancreatic CSCs. Pancreatic cancer sphere cultured from the CFPAC-1 cells showed elevated expression of PAUF and pluripotent stemness genes (Oct4, Nanog, Stat3, and Sox2), and the mRNA of PAUF were increased in CD44+CD24+ESA+ pancreatic CSCs...
July 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28756660/spectroscopy-and-dft-calculations-of-a-flavo-diiron-enzyme-implicate-new-diiron-site-structures
#16
Andrew C Weitz, Nitai Giri, Jonathan D Caranto, Donald M Kurtz, Emile L Bominaar, Michael P Hendrich
Flavo-diiron proteins (FDPs) are non-heme iron containing enzymes that are widespread in anaerobic bacteria, archaea, and protozoa, serving as the terminal components to dioxygen and nitric oxide reductive scavenging pathways in these organisms. FDPs contain a dinuclear iron active site similar to that in hemerythrin, ribonucleotide reductase, and methane monooxygenase, all of which can bind NO and O2. However, only FDP competently turns over NO to N2O. Here, EPR and Mössbauer spectroscopies allow electronic characterization of the diferric and diferrous species of FDP...
August 16, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28750923/didox-3-4-dihydroxybenzohydroxamic-acid-suppresses-il-33-induced-cytokine-production-in-primary-mouse-mast-cells
#17
Heather L Caslin, Jamie Josephine Avila McLeod, Andrew J Spence, Amina Abdul Qayum, Elizabeth Motunrayo Kolawole, Marcela T Taruselli, Anuya Paranjape, Howard L Elford, John J Ryan
While IgE is considered the primary mediator of mast cell activation, IL-33 contributes substantially in asthma, allergic rhinitis, and atopic dermatitis. To develop effective treatments for allergic disease, it is important to understand the role of therapeutic agents on IL-33 activation. We examined the effect of Didox (3,4-dihydroxybenzohydroxamic acid), an antioxidant and ribonucleotide reductase (RNR) inhibitor, on IL-33-mediated mast cell activation. Didox suppressed IL-6, IL-13, TNF, and MIP-1α (CCL3) production in bone marrow derived mast cells following IL-33 activation...
September 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28745337/understanding-the-metabolism-of-the-anticancer-drug-triapine-electrochemical-oxidation-microsomal-incubation-and-in-vivo-analysis-using-lc-hrms
#18
Karla Pelivan, Lisa Frensemeier, Uwe Karst, Gunda Koellensperger, Bjoern Bielec, Sonja Hager, Petra Heffeter, Bernhard K Keppler, Christian R Kowol
α-N-Heterocyclic thiosemicarbazones are among the most promising ribonucleotide reductase inhibitors identified so far. Triapine, the most prominent representative of this class of substances, has been investigated in multiple phase I and II clinical trials. With regard to clinical practice, Triapine showed activity against hematological diseases, but ineffectiveness against a variety of solid tumors. However, the reasons are still vague and the amount of ADME (absorption, distribution, metabolism and excretion) data for Triapine available in the literature is very limited...
July 26, 2017: Analyst
https://www.readbyqxmd.com/read/28743817/bacterial-signaling-nucleotides-inhibit-yeast-cell-growth-by-impacting-mitochondrial-and-other-specifically-eukaryotic-functions
#19
Andy Hesketh, Marta Vergnano, Chris Wan, Stephen G Oliver
We have engineered Saccharomyces cerevisiae to inducibly synthesize the prokaryotic signaling nucleotides cyclic di-GMP (cdiGMP), cdiAMP, and ppGpp in order to characterize the range of effects these nucleotides exert on eukaryotic cell function during bacterial pathogenesis. Synthetic genetic array (SGA) and transcriptome analyses indicated that, while these compounds elicit some common reactions in yeast, there are also complex and distinctive responses to each of the three nucleotides. All three are capable of inhibiting eukaryotic cell growth, with the guanine nucleotides exhibiting stronger effects than cdiAMP...
July 25, 2017: MBio
https://www.readbyqxmd.com/read/28735680/dynamic-control-of-dntp-synthesis-in-early-embryos
#20
Yonghyun Song, Robert A Marmion, Junyoung O Park, Debopriyo Biswas, Joshua D Rabinowitz, Stanislav Y Shvartsman
Exponential increase of cell numbers in early embryos requires large amounts of DNA precursors (deoxyribonucleoside triphosphates (dNTPs)). Little is understood about how embryos satisfy this demand. We examined dNTP metabolism in the early Drosophila embryo, in which gastrulation is preceded by 13 sequential nuclear cleavages within only 2 hr of fertilization. Surprisingly, despite the breakneck speed at which Drosophila embryos synthesize DNA, maternally deposited dNTPs can generate less than half of the genomes needed to reach gastrulation...
August 7, 2017: Developmental Cell
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