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Ribonucleotide reductase

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https://www.readbyqxmd.com/read/28521448/clinical-implications-of-ribonucleotide-reductase-subunit-m1-in-patients-with-pancreatic-cancer-who-undergo-curative-resection-followed-by-adjuvant-chemotherapy-with-gemcitabine
#1
Toru Aoyama, Yohei Miyagi, Masaaki Murakawa, Koichiro Yamaoku, Yosuke Atsumi, Manabu Shiozawa, Makoto Ueno, Manabu Morimoto, Takashi Oshima, Norio Yukawa, Takaki Yoshikawa, Yasushi Rino, Munetaka Masuda, Soichiro Morinaga
To the best of our knowledge, the clinical implications of using ribonucleoside reductase subunit M1 (RRM1) in patients who undergo curative resection and adjuvant chemotherapy have not been established. In the present study, the clinical data from 101 consecutive patients who underwent macroscopically curative resection, and who received adjuvant gemcitabine chemotherapy for pancreatic cancer at the Kanagawa Cancer Centre (Yokohama, Kanagawa, Japan) between April 2005 and December 2014 were retrospectively analyzed...
May 2017: Oncology Letters
https://www.readbyqxmd.com/read/28515324/the-diferric-tyrosyl-radical-cluster-of-ribonucleotide-reductase-and-cytosolic-iron-sulfur-clusters-have-distinct-and-similar-biogenesis-requirements
#2
Haoran Li, Martin Stümpfig, Caiguo Zhang, Xiuxiang An, JoAnne Stubbe, Roland Lill, Mingxia Huang
How each metalloprotein assembles the correct metal at the proper binding site presents challenges to the cell. The di-iron enzyme ribonucleotide reductase (RNR) uses a diferric-tyrosyl radical (Fe(III)2-Y·) cofactor to initiate nucleotide reduction. Assembly of this cofactor requires O2, Fe(II), and a reducing equivalent. Recent studies show that RNR cofactor biosynthesis shares the same source of iron, in the form of [2Fe-2S]-GSH2 from the monothiol glutaredoxin Grx3/4, and the same electron source, in the form of the Dre2-Tah18 electron transfer chain, with the cytosolic iron-sulfur protein assembly (CIA) machinery required for maturation of [4Fe-4S] clusters in cytosolic and nuclear proteins...
May 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28512059/genome-scale-metabolic-network-of-cordyceps-militaris-useful-for-comparative-analysis-of-entomopathogenic-fungi
#3
Wanwipa Vongsangnak, Nachon Raethong, Warasinee Mujchariyakul, Nam Ninh Nguyen, Hon Wai Leong, Kobkul Laoteng
The first genome-scale metabolic network of Cordyceps militaris (iWV1170) was constructed representing its whole metabolisms, which consisted of 894 metabolites and 1,267 metabolic reactions across five compartments, including the plasma membrane, cytoplasm, mitochondria, peroxisome and extracellular space. The iWV1170 could be exploited to explain its phenotypes of growth ability, cordycepin and other metabolites production on various substrates. A high number of genes encoding extracellular enzymes for degradation of complex carbohydrates, lipids and proteins were existed in C...
May 13, 2017: Gene
https://www.readbyqxmd.com/read/28507282/p53-suppresses-ribonucleotide-reductase-via-inhibiting-mtorc1
#4
Zhengfu He, Xing Hu, Weijin Liu, Adrienne Dorrance, Ramiro Garzon, Peter J Houghton, Changxian Shen
Balanced deoxyribonucleotides pools are essential for cell survival and genome stability. Ribonucleotide reductase is the rate-limiting enzyme for the production of deoxyribonucleotides. We report here that p53 suppresses ribonucleotide reductase subunit 1 (RRM1) and 2 (RRM2) via inhibiting mammalian target of rapamycin complex 1 (mTORC1). In vitro, cancer cell lines and mouse embryonic fibroblast cells were treated with different concentrations of pharmacological inhibitors for different times. In vivo, rhabdomyosarcoma Rh30 cell tumor-bearing mice were treated with rapamycin or AZD8055...
April 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28502800/microrna-211-regulates-oxidative-phosphorylation-and-energy-metabolism-in-human-vitiligo
#5
Anupama Sahoo, Bongyong Lee, Katia Boniface, Julien Seneschal, Sanjaya K Sahoo, Tatsuya Seki, Chunyan Wang, Soumen Das, Xianlin Han, Michael Steppie, Sudipta Seal, Alain Taieb, Ranjan J Perera
Vitiligo is a common, chronic skin disorder characterized by loss of epidermal melanocytes and progressive depigmentation. Vitiligo has complex immune, genetic, environmental, and biochemical etiology, but the exact molecular mechanisms of vitiligo development and progression, particularly those related to metabolic control, are poorly understood. Here we characterized the human vitiligo cell line PIG3V and the normal human melanocytes, HEM-l by RNA-sequencing (RNA-seq), targeted metabolomics, and shotgun lipidomics...
May 11, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28495531/the-forkhead-like-transcription-factor-fhl1p-maintains-yeast-replicative-lifespan-by-regulating-ribonucleotide-reductase-1-rnr1-gene-transcription
#6
Akiko Tai, Yuka Kamei, Yukio Mukai
In eukaryotes, numerous genetic factors contribute to the lifespan including metabolic enzymes, signal transducers, and transcription factors. As previously reported, the forkhead-like transcription factor (FHL1) gene was required for yeast replicative lifespan and cell proliferation. To determine how Fhl1p regulates the lifespan, we performed a DNA microarray analysis of a heterozygous diploid strain deleted for FHL1. We discovered numerous Fhl1p-target genes, which were then screened for lifespan-regulating activity...
June 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28487404/long-range-proton-coupled-electron-transfer-in-the-escherichia-coli-class-ia-ribonucleotide-reductase
#7
REVIEW
Steven Y Reece, Mohammad R Seyedsayamdost
Escherichia coli class Ia ribonucleotide reductase (RNR) catalyzes the conversion of nucleotides to 2'-deoxynucleotides using a radical mechanism. Each turnover requires radical transfer from an assembled diferric tyrosyl radical (Y•) cofactor to the enzyme active site over 35 Å away. This unprecedented reaction occurs via an amino acid radical hopping pathway spanning two protein subunits. To study the mechanism of radical transport in RNR, a suite of biochemical approaches have been developed, such as site-directed incorporation of unnatural amino acids with altered electronic properties and photochemical generation of radical intermediates...
May 9, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/28472930/three-novel-pseudomonas-phages-isolated-from-composting-provide-insights-into-the-evolution-and-diversity-of-tailed-phages
#8
Deyvid Amgarten, Layla Farage Martins, Karen Cristina Lombardi, Luciana Principal Antunes, Ana Paula Silva de Souza, Gianlucca Gonçalves Nicastro, Elliott Watanabe Kitajima, Ronaldo Bento Quaggio, Chris Upton, João Carlos Setubal, Aline Maria da Silva
BACKGROUND: Among viruses, bacteriophages are a group of special interest due to their capacity of infecting bacteria that are important for biotechnology and human health. Composting is a microbial-driven process in which complex organic matter is converted into humus-like substances. In thermophilic composting, the degradation activity is carried out primarily by bacteria and little is known about the presence and role of bacteriophages in this process. RESULTS: Using Pseudomonas aeruginosa as host, we isolated three new phages from a composting operation at the Sao Paulo Zoo Park (Brazil)...
May 4, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28469953/microrna-1468-5p-inhibits-glioma-cell-proliferation-and-induces-cell-cycle-arrest-by-targeting-rrm1
#9
Kuan Jiang, Tongle Zhi, Wenhui Xu, Xiupeng Xu, Weining Wu, Tianfu Yu, Er Nie, Xu Zhou, Zhongyuan Bao, Xin Jin, Junxia Zhang, Yingyi Wang, Ning Liu
MicroRNAs are associated with different types of cancers. In this study, we found that miR-1468-5p could inhibit growth and cell cycle progression in glioma by targeting ribonucleotide reductase large subunit M1 (RRM1). First, we analyzed miR-1468-5p expression in different glioma grades and the prognostic significance of its expression in glioblastoma multiform patients from the Chinese Glioma Genome Atlas. Then, we expressed miR-1468-5p in U87 and U251 cells and assessed the effects on proliferation and cell cycle progression using cell counting kit-8, colony formation, EdU and flow cytometry assays...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28468907/gsk-3%C3%A3-homolog-rim11-and-the-histone-deacetylase-complex-ume6-sin3-rpd3-are-involved-in-replication-stress-response-caused-by-defects-in-dna2
#10
Annie Albert Demin, Miju Lee, Chul-Hwan Lee, Yeon-Soo Seo
Lagging strand synthesis is mechanistically far more complicated than leading strand synthesis, since it involves multi-step processes and requires considerably more enzymes and protein factors. Due to this complexity, multiple fail-safe factors are required to ensure successful replication of the lagging strand DNA. We attempted to identify novel factors that are required in the absence of the helicase activity of Dna2, an essential enzyme in Okazaki fragment maturation. In this paper, we identified Rim11, a GSK-3ß kinase homolog, as a multicopy suppressor of dna2 helicase-dead mutant (dna2-K1080E)...
May 3, 2017: Genetics
https://www.readbyqxmd.com/read/28459467/ribonucleotide-reductase-represents-a-novel-therapeutic-target-in-primary-effusion-lymphoma
#11
L Dai, Z Lin, J Qiao, Y Chen, E K Flemington, Z Qin
Primary effusion lymphoma (PEL) is a highly aggressive B-cell malignancy that is closely associated with one of oncogenic viruses infection, Kaposi's sarcoma-associated herpesvirus. PEL prognosis is poor and patients barely survive >6 months even following active chemotherapy interventions. There is therefore an urgent need to discover more effective targets for PEL management. We recently found that the ribonucleotide reductase (RR) subunit M2 is potentially regulated by the key oncogenic hepatocyte growth factor/c-MET pathway in PEL...
May 1, 2017: Oncogene
https://www.readbyqxmd.com/read/28442502/ribonucleotide-reductase-large-subunit-rrm1-as-a-novel-therapeutic-target-in-multiple-myeloma
#12
Morihiko Sagawa, Hiroto Ohguchi, Takeshi Harada, Mehmet K Samur, Yu-Tzu Tai, Nikhil C Munshi, Masahiro Kizaki, Teru Hideshima, Kenneth C Anderson
Purpose: To investigate the biologic and clinical significance of ribonucleotide reductase (RR) in multiple myeloma (MM). <p>Experimental Design: We assessed the impact of RR expression on patient outcome in MM. We then characterized the effect of genetic and pharmacological inhibition of RRM1 on MM growth and survival using siRNA and clofarabine (CLO), respectively, both in vitro and in vivo mouse xenograft model.</p> <p>Results: Newly diagnosed MM patients with higher RRM1 expression have shortened survival...
April 25, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28441348/deoxynucleoside-salvage-in-fission-yeast-allows-rescue-of-ribonucleotide-reductase-deficiency-but-not-spd1-mediated-inhibition-of-replication
#13
Oliver Fleck, Ulrik Fahnøe, Katrine Vyff Løvschal, Marie-Fabrice Uwamahoro Gasasira, Irina N Marinova, Birthe B Kragelund, Antony M Carr, Edgar Hartsuiker, Christian Holmberg, Olaf Nielsen
In fission yeast, the small, intrinsically disordered protein S-phase delaying protein 1 (Spd1) blocks DNA replication and causes checkpoint activation at least in part, by inhibiting the enzyme ribonucleotide reductase, which is responsible for the synthesis of DNA. The CRL4(Cdt2) E3 ubiquitin ligase mediates degradation of Spd1 and the related protein Spd2 at S phase of the cell cycle. We have generated a conditional allele of CRL4(Cdt2), by expressing the highly unstable substrate-recruiting protein Cdt2 from a repressible promoter...
April 25, 2017: Genes
https://www.readbyqxmd.com/read/28440428/inhibition-of-atr-potentiates-the-cytotoxic-effect-of-gemcitabine-on-pancreatic-cancer-cells-through-enhancement-of-dna-damage-and-abrogation-of-ribonucleotide-reductase-induction-by-gemcitabine
#14
Shuang Liu, Yubin Ge, Tingting Wang, Holly Edwards, Qihang Ren, Yiqun Jiang, Chengshi Quan, Guan Wang
Pancreatic cancer is a highly malignant disease with a dismal prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line treatment for patients with advanced disease, although its efficacy is very limited, mainly due to drug resistance. Ataxia telangiectasia and Rad3-related (ATR) plays a critical role in the DNA damage response (DDR) which has been implicated in GEM resistance. Thus, targeting ATR represents a promising approach to enhance GEM antitumor activity. In the present study, we tested the antitumor activity of AZ20, a novel ATR-selective inhibitor, alone or combined with GEM in 5 pancreatic cancer cell lines...
April 19, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28436563/an-in-vitro-system-for-measuring-genotoxicity-mediated-by-human-cyp3a4-in-saccharomyces-cerevisiae
#15
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 )...
May 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
#16
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
#17
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
#18
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
#19
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
#20
Vladimir Domkin, Andrei Chabes
No abstract text is available yet for this article.
April 7, 2017: Scientific Reports
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