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Ribonucleotide reductase

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https://www.readbyqxmd.com/read/28436563/an-in-vitro-system-for-measuring-genotoxicity-mediated-by-human-cyp3a4-in-saccharomyces-cerevisiae
#1
Michael Fasullo, Julian Freedland, Nicholas St John, Cinzia Cera, Patricia Egner, Matthew Hartog, Xinxin Ding
P450 activity is required to metabolically activate many chemical carcinogens, rendering them highly genotoxic. CYP3A4 is the most abundantly expressed P450 enzyme in the liver, accounting for most drug metabolism and constituting 50% of all hepatic P450 activity. CYP3A4 is also expressed in extrahepatic tissues, including the intestine. However, the role of CYP3A4 in activating chemical carcinogens into potent genotoxins is unclear. To facilitate efforts to determine whether CYP3A4, per se, can activate carcinogens into potent genotoxins, we expressed human CYP3A4 in the DNA-repair mutant (rad4 rad51) strain of budding yeast Saccharomyces cerevisiae and tested the novel, recombinant yeast strain for ability to report CYP3A4-mediated genotoxicity of a well-known genotoxin, aflatoxin B1 (AFB1 )...
April 24, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28421163/phase-i-trial-of-triapine-cisplatin-paclitaxel-chemotherapy-for-advanced-stage-or-metastatic-solid-tumor-cancers
#2
Charles A Kunos, Edward Chu, Della Makower, Andreas Kaubisch, Mario Sznol, Susan Percy Ivy
Ribonucleotide reductase (RNR) is an enzyme involved in the de novo synthesis of deoxyribonucleotides, which are critical for DNA replication and DNA repair. Triapine is a small-molecule RNR inhibitor. A phase I trial studied the safety of triapine in combination with cisplatin-paclitaxel in patients with advanced stage or metastatic solid tumor cancers in an effort to capitalize on disrupted DNA damage repair. A total of 13 patients with various previously treated cancers were given a 96-h continuous intravenous (i...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28416670/alterations-in-cellular-metabolism-triggered-by-ura7-or-gln3-inactivation-cause-imbalanced-dntp-pools-and-increased-mutagenesis
#3
Tobias T Schmidt, Gloria Reyes, Kerstin Gries, Cemile Ümran Ceylan, Sushma Sharma, Matthias Meurer, Michael Knop, Andrei Chabes, Hans Hombauer
Eukaryotic DNA replication fidelity relies on the concerted action of DNA polymerase nucleotide selectivity, proofreading activity, and DNA mismatch repair (MMR). Nucleotide selectivity and proofreading are affected by the balance and concentration of deoxyribonucleotide (dNTP) pools, which are strictly regulated by ribonucleotide reductase (RNR). Mutations preventing DNA polymerase proofreading activity or MMR function cause mutator phenotypes and consequently increased cancer susceptibility. To identify genes not previously linked to high-fidelity DNA replication, we conducted a genome-wide screen in Saccharomyces cerevisiae using DNA polymerase active-site mutants as a "sensitized mutator background...
April 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28416140/ribonucleotide-reductase-requires-subunit-switching-in-hypoxia-to-maintain-dna-replication
#4
Iosifina P Foskolou, Christian Jorgensen, Katarzyna B Leszczynska, Monica M Olcina, Hanna Tarhonskaya, Bauke Haisma, Vincenzo D'Angiolella, William K Myers, Carmen Domene, Emily Flashman, Ester M Hammond
Cells exposed to hypoxia experience replication stress but do not accumulate DNA damage, suggesting sustained DNA replication. Ribonucleotide reductase (RNR) is the only enzyme capable of de novo synthesis of deoxyribonucleotide triphosphates (dNTPs). However, oxygen is an essential cofactor for mammalian RNR (RRM1/RRM2 and RRM1/RRM2B), leading us to question the source of dNTPs in hypoxia. Here, we show that the RRM1/RRM2B enzyme is capable of retaining activity in hypoxia and therefore is favored over RRM1/RRM2 in order to preserve ongoing replication and avoid the accumulation of DNA damage...
April 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28411237/physical-interaction-between-human-ribonucleotide-reductase-large-subunit-and-thioredoxin-increases-colorectal-cancer-malignancy
#5
Meng Lou, Qian Liu, Guoping Ren, Jiling Zeng, Xueping Xiang, Yongfeng Ding, Qinghui Lin, Tingting Zhong, Xia Liu, Lijun Zhu, Hongyan Qi, Jing Shen, Haoran Li, Jimin Shao
Ribonucleotide reductase (RR) is the rate-limiting enzyme in DNA synthesis by catalyzing the reduction of ribonucleotides to deoxyribonucleotides. During each enzymatic turnover, reduction of the active site disulfide in the catalytic large subunit is performed by a pair of shuttle cysteine residues in its C-terminal tail. Thioredoxin (Trx) and Glutaredoxin (Grx) are ubiquitous redox proteins, catalyzing thiol-disulfide exchange reactions. Here, immunohistochemical examination of clinical colorectal cancer (CRC) specimens revealed that human thioredoxin1 (hTrx1), but not human glutaredoxin1 (hGrx1), was upregulated along with human RR large subunit (RRM1) in cancer tissues, and the expression levels of both proteins were correlated with cancer malignancy stage...
April 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28387227/corrigendum-phosphines-are-ribonucleotide-reductase-reductants-that-act-via-c-terminal-cysteines-similar-to-thioredoxins-and-glutaredoxins
#6
Vladimir Domkin, Andrei Chabes
No abstract text is available yet for this article.
April 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28377506/heme-deficiency-sensitizes-yeast-cells-to-oxidative-stress-induced-by-hydroxyurea
#7
Amanpreet Singh, Yong-Jie Xu
Hydroxyurea (HU) has a long history of clinical and scientific use as an antiviral, antibacterial, and antitumor agent. It inhibits ribonucleotide reductase and reversibly arrests cells in S phase. However, high concentrations or prolonged treatment with low doses of HU can cause cell lethality. Although the cytotoxicity of HU may significantly contribute to its therapeutic effects, the underlying mechanisms remain poorly understood. We have previously shown that HU can induce cytokinesis arrest in the erg11-1 mutant of fission yeast, which has a partial defect in the biosynthesis of fungal membrane sterol ergosterol (1)...
April 4, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28377505/glutamate-52-%C3%AE-at-the-%C3%AE-%C3%AE-subunit-interface-of-e-coli-class-ia-ribonucleotide-reductase-is-essential-for-conformational-gating-of-radical-transfer
#8
Qinghui Lin, Mackenzie J Parker, Alexander T Taguchi, Kanchana Ravichandran, Albert Kim, Gyunghoon Kang, Jimin Shao, Catherine L Drennan, JoAnne Stubbe
Ribonucleotide reductases (RNRs) catalyze the conversion of nucleoside diphosphate substrates (S) to deoxynucleotides with allosteric effectors (e) controlling their relative ratios and amounts, crucial for fidelity of DNA replication and repair. E. coli class Ia RNR is composed of α and β subunits that form a transient, active α2β2 complex. The E. coli RNR is rate-limited by S/e-dependent conformational change(s) that trigger the radical initiation step through a pathway of 35 Å across the subunit (α/β) interface...
April 4, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28332829/impact-of-peg-chain-length-on-the-physical-properties-and-bioactivity-of-pegylated-chitosan-sirna-nanoparticles-in-vitro-and-in-vivo
#9
Chuanxu Yang, Shan Gao, Frederik Dagnæs-Hansen, Maria Jakobsen, Jørgen Kjems
PEGylation of cationic polyplexes is a promising approach to enhance the stability and reduce unspecific interaction with biological components. Herein, we systematically investigate the impact of PEGylation on physical and biological properties of chitosan/siRNA polyplexes. A series of chitosan-PEG copolymers (CS-PEG2k, CS-PEG5k and CS-PEG10k) were synthesized with similar PEG mass content but with different molecular weight. PEGylation with higher molecular weight and less grafting degree resulted in smaller and more compacted nanoparticles with relatively higher surface charge...
April 3, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28332661/geometrical-properties-of-the-manganese-iv-iron-iii-cofactor-of-chlamydia-trachomatis-ribonucleotide-reductase-unveiled-by-simulations-of-xas-spectra
#10
Eduardo M Sproviero
Using simulations of Mn/Fe K-edge X-ray absorption spectroscopy (XAS), combined with DFT-optimized structural models and direct comparisons with available experimental data, we determine geometrical and electronic properties of the Mn-Fe active site of Chlamydia trachomatis (Ct) of ribonucleotide reductase (RNR). In the post-edge XAS energy range, we use extended X-ray absorption fine structure (EXAFS) data, to acquire absorber-scatterer geometrical information around each absorber metal center. For this task, we apply a protocol that evaluates Debye-Waller factors in scattering paths instead of scattering shells to fit the experimental EXAFS...
March 23, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28327155/vasohibin-2-reduces-chemosensitivity-to-gemcitabine-in-pancreatic-cancer-cells-via-jun-proto-oncogene-dependent-transactivation-of-ribonucleotide-reductase-regulatory-subunit-m2
#11
Min Tu, Haifeng Li, Nan Lv, Chunhua Xi, Zipeng Lu, Jishu Wei, Jianmin Chen, Feng Guo, Kuirong Jiang, Guoxin Song, Wentao Gao, Yi Miao
BACKGROUND: Vasohibin 2 (VASH2) has previously been identified as an agiogenenic factor and a cancer related protein. Here we investigated the association of VASH2 expression and chemoresistance in pancreatic cancer. METHODS: Immunohistochemical staining for VASH2 was performed on 102 human pancreatic cancer samples. Pancreatic cancer cell line models exhibiting overexpression or knockdown of VASH2 were generated. Gene expression analyses were carried out to determine genes differentially regulated by VASH2...
March 21, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28324147/genotoxicity-kinetics-in-murine-normoblasts-as-an-approach-for-the-in-vivo-action-of-difluorodeoxycytidine
#12
Pedro Morales-Ramírez, Teresita Vallarino-Kelly, Virginia Cruz-Vallejo
PURPOSE: This study analyzed the kinetics of in vivo micronucleus induction in normoblasts by determining the kinetics of difluorodeoxycytidine (dFdC)-induced micronucleated polychromatic erythrocytes (MN-PCEs) in the peripheral blood of mice. The kinetic indexes of MN-PCE induction of dFdC were correlated with the previously reported mechanisms DNA damage induction by this compound. In general, this study aimed to establish an in vivo approach for discerning the processes underlying micronucleus induction by antineoplastic agents or mutagens in general...
March 21, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28322141/lessons-learned-from-gemcitabine-impact-of-therapeutic-carrier-systems-and-gemcitabine-s-drug-conjugates-on-cancer-therapy
#13
REVIEW
Sathish Dyawanapelly, Animesh Kumar, Manish K Chourasia
Currently, drug delivery systems have a high impact in cancer therapy and are receiving more attention than conventional cancer treatment modalities. Compared with current cancer therapies, gemcitabine (2', 2'-difluoro-2'-deoxycytidine) has been proven to be an effective chemotherapeutic agent against pancreatic, colon, bladder, breast, ovarian, non-small-cell lung, and head and neck cancers in combination with other anticancer agents. To improve the safety and efficacy of cytotoxic drugs, several drug delivery systems have been explored...
2017: Critical Reviews in Therapeutic Drug Carrier Systems
https://www.readbyqxmd.com/read/28289079/deletion-of-f4l-ribonucleotide-reductase-in-vaccinia-virus-produces-a-selective-oncolytic-virus-and-promotes-anti-tumor-immunity-with-superior-safety-in-bladder-cancer-models
#14
Kyle G Potts, Chad R Irwin, Nicole A Favis, Desmond B Pink, Krista M Vincent, John D Lewis, Ronald B Moore, Mary M Hitt, David H Evans
Bladder cancer has a recurrence rate of up to 80% and many patients require multiple treatments that often fail, eventually leading to disease progression. In particular, standard of care for high-grade disease, Bacillus Calmette-Guérin (BCG), fails in 30% of patients. We have generated a novel oncolytic vaccinia virus (VACV) by mutating the F4L gene that encodes the virus homolog of the cell-cycle-regulated small subunit of ribonucleotide reductase (RRM2). The F4L-deleted VACVs are highly attenuated in normal tissues, and since cancer cells commonly express elevated RRM2 levels, have tumor-selective replication and cell killing...
March 13, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28253714/microarray-expression-analysis-of-mycn-amplified-neuroblastoma-cells-after-inhibition-of-cdk2
#15
H Song, F Wu, S Li, Z Wang, X Liu, Y Cui, C Lin
The study was aimed to explore the underlying molecular mechanisms of CDK2 inhibition in neuroblastoma by bioinformatics analysis. Gene expression profile GSE16480 was downloaded from the Gene Expression Omnibus. The differentially expressed genes (DEGs) were identified from IMR32 between each time point and average expression of all time points. Gene significance was calculated using dSVDsig algorithm of dnet package. Protein-protein interaction (PPI) network was built. Then, integrated with gene significance, a core PPI network was detected by dNetPipeline algorithm in dnet package...
March 3, 2017: Neoplasma
https://www.readbyqxmd.com/read/28252952/new-iminodiacetate-thiosemicarbazone-hybrids-and-their-copper-ii-complexes-are-potential-ribonucleotide-reductase-r2-inhibitors-with-high-antiproliferative-activity
#16
Mirela F Zaltariov, Marta Hammerstad, Homayon J Arabshahi, Katarina Jovanović, Klaus W Richter, Maria Cazacu, Sergiu Shova, Mihaela Balan, Niels H Andersen, Siniša Radulović, Jóhannes Reynisson, K Kristoffer Andersson, Vladimir B Arion
As ribonucleotide reductase (RNR) plays a crucial role in nucleic acid metabolism, it is an important target for anticancer therapy. The thiosemicarbazone Triapine is an efficient R2 inhibitor, which has entered ∼20 clinical trials. Thiosemicarbazones are supposed to exert their biological effects through effectively binding transition-metal ions. In this study, six iminodiacetate-thiosemicarbazones able to form transition-metal complexes, as well as six dicopper(II) complexes, were synthesized and fully characterized by analytical, spectroscopic techniques (IR, UV-vis; (1)H and (13)C NMR), electrospray ionization mass spectrometry, and X-ray diffraction...
March 2, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28250468/drop-on-demand-sample-delivery-for-studying-biocatalysts-in-action-at-x-ray-free-electron-lasers
#17
Franklin D Fuller, Sheraz Gul, Ruchira Chatterjee, E Sethe Burgie, Iris D Young, Hugo Lebrette, Vivek Srinivas, Aaron S Brewster, Tara Michels-Clark, Jonathan A Clinger, Babak Andi, Mohamed Ibrahim, Ernest Pastor, Casper de Lichtenberg, Rana Hussein, Christopher J Pollock, Miao Zhang, Claudiu A Stan, Thomas Kroll, Thomas Fransson, Clemens Weninger, Markus Kubin, Pierre Aller, Louise Lassalle, Philipp Bräuer, Mitchell D Miller, Muhamed Amin, Sergey Koroidov, Christian G Roessler, Marc Allaire, Raymond G Sierra, Peter T Docker, James M Glownia, Silke Nelson, Jason E Koglin, Diling Zhu, Matthieu Chollet, Sanghoon Song, Henrik Lemke, Mengning Liang, Dimosthenis Sokaras, Roberto Alonso-Mori, Athina Zouni, Johannes Messinger, Uwe Bergmann, Amie K Boal, J Martin Bollinger, Carsten Krebs, Martin Högbom, George N Phillips, Richard D Vierstra, Nicholas K Sauter, Allen M Orville, Jan Kern, Vittal K Yachandra, Junko Yano
X-ray crystallography at X-ray free-electron laser sources is a powerful method for studying macromolecules at biologically relevant temperatures. Moreover, when combined with complementary techniques like X-ray emission spectroscopy, both global structures and chemical properties of metalloenzymes can be obtained concurrently, providing insights into the interplay between the protein structure and dynamics and the chemistry at an active site. The implementation of such a multimodal approach can be compromised by conflicting requirements to optimize each individual method...
April 2017: Nature Methods
https://www.readbyqxmd.com/read/28220209/s-phase-checkpoint-regulations-that-preserve-replication-and-chromosome-integrity-upon-dntp-depletion
#18
REVIEW
Michele Giannattasio, Dana Branzei
DNA replication stress, an important source of genomic instability, arises upon different types of DNA replication perturbations, including those that stall replication fork progression. Inhibitors of the cellular pool of deoxynucleotide triphosphates (dNTPs) slow down DNA synthesis throughout the genome. Following depletion of dNTPs, the highly conserved replication checkpoint kinase pathway, also known as the S-phase checkpoint, preserves the functionality and structure of stalled DNA replication forks and prevents chromosome fragmentation...
February 20, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28196013/prognostic-implications-of-expression-profiling-for-gemcitabine-related-genes-hent1-dck-rrm1-rrm2-in-patients-with-resectable-pancreatic-adenocarcinoma-receiving-adjuvant-chemotherapy
#19
Marek Sierzega, Radosław Pach, Piotr Kulig, Janusz Legutko, Jan Kulig
OBJECTIVES: The aim of this study was to examine the relevance of expression profiling of 4 genes involved in the action of gemcitabine among patients with pancreatic ductal-cell adenocarcinoma (PDAC). METHODS: A group of 100 patients who underwent pancreatic resections for PDAC and received adjuvant chemotherapy with gemcitabine between 2007 and 2010 was identified. Expression of mRNAs for human equilibrative nucleoside transporter 1 (hENT1), ribonucleotide reductase subunits (RRM1, RRM2), and deoxycytidine kinase (dCK) was examined by quantitative real-time polymerase chain reaction, normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and dichotomized into groups of low and moderate/high expression levels grouped by tertiles...
May 2017: Pancreas
https://www.readbyqxmd.com/read/28171730/formal-reduction-potentials-of-difluorotyrosine-and-trifluorotyrosine-protein-residues-defining-the-thermodynamics-of-multistep-radical-transfer
#20
Kanchana R Ravichandran, Allan B Zong, Alexander T Taguchi, Daniel G Nocera, JoAnne Stubbe, Cecilia Tommos
Redox-active tyrosines (Ys) play essential roles in enzymes involved in primary metabolism including energy transduction and deoxynucleotide production catalyzed by ribonucleotide reductases (RNRs). Thermodynamic characterization of Ys in solution and in proteins remains a challenge due to the high reduction potentials involved and the reactive nature of the radical state. The structurally characterized α3Y model protein has allowed the first determination of formal reduction potentials (E°') for a Y residing within a protein (Berry, B...
February 21, 2017: Journal of the American Chemical Society
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