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Ribonucleotide reductase

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https://www.readbyqxmd.com/read/29138305/manipulating-the-bacterial-cell-cycle-and-cell-size-by-titrating-the-expression-of-ribonucleotide-reductase
#1
Manlu Zhu, Xiongfeng Dai, Weilun Guo, Zengxiang Ge, Mingxuan Yang, Haikuan Wang, Yi-Ping Wang
Understanding how bacteria coordinate growth with cell cycle events to maintain cell size homeostasis remains a grand challenge in biology. The period of chromosome replication (C period) is a key stage in the bacterial cell cycle. However, the mechanism of in vivo regulation of the C period remains unclear. In this study, we found that titration of the expression of ribonucleotide reductase (RNR), which changes the intracellular deoxynucleoside triphosphate (dNTP) pools, enables significant perturbations of the C period, leading to a substantial change in cell size and DNA content...
November 14, 2017: MBio
https://www.readbyqxmd.com/read/29123070/redox-sensitive-alteration-of-replisome-architecture-safeguards-genome-integrity
#2
Kumar Somyajit, Rajat Gupta, Hana Sedlackova, Kai John Neelsen, Fena Ochs, Maj-Britt Rask, Chunaram Choudhary, Jiri Lukas
DNA replication requires coordination between replication fork progression and deoxynucleotide triphosphate (dNTP)-generating metabolic pathways. We find that perturbation of ribonucleotide reductase (RNR) in humans elevates reactive oxygen species (ROS) that are detected by peroxiredoxin 2 (PRDX2). In the oligomeric state, PRDX2 forms a replisome-associated ROS sensor, which binds the fork accelerator TIMELESS when exposed to low levels of ROS. Elevated ROS levels generated by RNR attenuation disrupt oligomerized PRDX2 to smaller subunits, whose dissociation from chromatin enforces the displacement of TIMELESS from the replisome...
November 10, 2017: Science
https://www.readbyqxmd.com/read/29119271/rnr1-s-role-in-telomere-elongation-cannot-be-replaced-by-rnr3-a-role-beyond-dntps
#3
REVIEW
André Maicher, Martin Kupiec
Telomeres, the nucleoprotein complexes at the end of eukaryotic chromosomes, protect them from degradation and ensure the replicative capacity of cells. In most human tumors and in budding yeast, telomere length is maintained by the activity of telomerase, an enzyme that adds dNTPs according to an internal RNA template. The dNTPs are generated with the help of the ribonucleotide reductase (RNR) complex. We have recently generated strains lacking the large subunit of RNR, Rnr1, which were kept viable by the expression of RNR complexes containing the Rnr1 homolog, Rnr3...
November 8, 2017: Current Genetics
https://www.readbyqxmd.com/read/29113399/dck-expression-a-potential-predictive-biomarker-in-the-adjuvant-gemcitabine-chemotherapy-for-biliary-tract-cancer-after-surgical-resection-results-from-a-phase-ii-study
#4
Sang Myung Woo, Kyong-Ah Yoon, Eun Kyung Hong, Weon Seo Park, Sung-Sik Han, Sang-Jae Park, Jungnam Joo, Eun Young Park, Ju Hee Lee, Yun-Hee Kim, Tae Hyun Kim, Woo Jin Lee
The role of adjuvant therapy following resection of biliary tract cancer (BTC) remains unclear. We therefore evaluated the feasibility and toxicity of adjuvant gemcitabine in patients with BTC. This clinical phase II trial was an open-label, single center, single-arm study. Within 8 weeks after gross complete resection of BTC, patients were started on intravenous infusions of gemcitabine 1000 mg/m(2) over 30 min on days 1, 8, and 15 of every 28-day cycle. Intratumoral expression of cytidine deaminase (CDA), human equilibrative transporter-1 (hENT1), deoxycytidine kinase (dCK) and ribonucleotide reductase subunit 1 (RRM1) was measured by immunohistochemistry...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29111571/n-4-aryl-substituted-thiosemicarbazones-derived-from-1-indanones-as-potential-anti-tumor-agents-for-breast-cancer-treatment
#5
A Sólimo, M C Soraires Santacruz, A I Loaiza Perez, E Bal de Kier Joffé, L M Finkielsztein, M A Callero
Breast cancer is the first cause of cancer death in women. Many patients are resistant to current therapies, and even those were sensitive at first may eventually become resistant later. Thiosemicarbazones (TSCs) are synthetic compounds that exhibit several pharmacological activities. In this study, we investigated the potential anti-tumor activity of a set of N(4) -arylsubstituted TSCs (N(4) -TSCs) on human breast cancer cell lines. Studies on the effect of N(4) -TSCs (T1, T2 and T3) were carried on MCF-7, MDA-MB 231 and BT 474 cell lines which differ in their expression of ER, PR and Her2/neu...
November 7, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29100320/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
#6
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...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29099956/recycling-drug-screen-repurposes-hydroxyurea-as-a-sensitizer-of-glioblastomas-to-temozolomide-targeting-de-novo-dna-synthesis-irrespective-of-molecular-subtype
#7
Jian Teng, Seyedali Hejazi, Lotte Hiddingh, Litia Carvalho, Mark de Gooijer, Hiroaki Wakimoto, Marco Barazas, Marie Tannous, Andrew S Chi, David P Noske, Pieter Wesseling, Thomas Wurdinger, Tracy T Batchelor, Bakhos A Tannous
Background: Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor. Standard-of-care treatment involves maximal surgical resection of the tumor followed by radiation and chemotherapy (temozolomide; TMZ). The five-year survival rate of patients with GBM is <10%, a colossal failure that has been partially attributed to intrinsic and/or acquired resistance to TMZ through MGMT (O6-methylguanine DNA methyltransferase) promoter methylation status in the tumor...
November 1, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/29069086/rnr1-but-not-rnr3-facilitates-the-sustained-telomerase-dependent-elongation-of-telomeres
#8
André Maicher, Inbal Gazy, Sushma Sharma, Lisette Marjavaara, Gilad Grinberg, Keren Shemesh, Andrei Chabes, Martin Kupiec
Ribonucleotide reductase (RNR) provides the precursors for the generation of dNTPs, which are required for DNA synthesis and repair. Here, we investigated the function of the major RNR subunits Rnr1 and Rnr3 in telomere elongation in budding yeast. We show that Rnr1 is essential for the sustained elongation of short telomeres by telomerase. In the absence of Rnr1, cells harbor very short, but functional, telomeres, which cannot become elongated by increased telomerase activity or by tethering of telomerase to telomeres...
October 2017: PLoS Genetics
https://www.readbyqxmd.com/read/29064667/manganese-oxygen-intermediates-in-o-o-bond-activation-and-hydrogen-atom-transfer-reactions
#9
Derek B Rice, Allyssa A Massie, Timothy A Jackson
Biological systems capitalize on the redox versatility of manganese to perform reactions involving dioxygen and its derivatives superoxide, hydrogen peroxide, and water. The reactions of manganese enzymes influence both human health and the global energy cycle. Important examples include the detoxification of reactive oxygen species by manganese superoxide dismutase, biosynthesis by manganese ribonucleotide reductase and manganese lipoxygenase, and water splitting by the oxygen-evolving complex of photosystem II...
October 24, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/29057303/rrm2b-an-oxygen-requiring-protein-with-a-role-in-hypoxia
#10
Iosifina P Foskolou, Ester M Hammond
How tumor cells adapt and survive under hypoxia significantly impacts patient prognosis. We recently demonstrated that the oxygen-requiring ribonucleotide reductase (RNR) enzyme, which provides cells with deoxyribonucleotides, responds to limited oxygen availability by switching small subunits from RRM2 to RRM2B. This property of RNR is essential for hypoxic cell viability and therefore contributes to the most aggressive and therapy-resistant fraction of tumors.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29054416/targeting-the-selenoprotein-thioredoxin-reductase-1-for-anticancer-therapy
#11
Elias S J Arnér
The cytosolic selenoprotein thioredoxin reductase 1 (TrxR1, encoded in human by TXNRD1) is implied to have several different roles in relation to cancer. Its physiologic functions may protect normal cells from carcinogenesis, but may also promote cancer progression if carcinogenesis nonetheless occurs. With distinct links to Nrf2 signaling, ribonucleotide reductase-dependent production of deoxyribonucleotides and its support of several antioxidant systems counteracting oxidative stress, the metabolic pathways regulated, and affected by TrxR1, are altogether of crucial importance in cancer...
2017: Advances in Cancer Research
https://www.readbyqxmd.com/read/29042684/a-single-point-mutation-in-class-iii-ribonucleotide-reductase-promoter-renders-pseudomonas-aeruginosa-pao1-inefficient-for-anaerobic-growth-and-infection
#12
Anna Crespo, Joan Gavaldà, Esther Julián, Eduard Torrents
Pseudomonas aeruginosa strain PAO1 has become the reference strain in many laboratories. One enzyme that is essential for its cell division is the ribonucleotide reductase (RNR) enzyme that supplies the deoxynucleotides required for DNA synthesis and repair. P. aeruginosa is one of the few microorganisms that encodes three different RNR classes (Ia, II and III) in its genome, enabling it to grow and adapt to diverse environmental conditions, including during infection. In this work, we demonstrate that a lack of RNR activity induces cell elongation in P...
October 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29037038/conformationally-dynamic-radical-transfer-within-ribonucleotide-reductase
#13
Brandon L Greene, Alexander T Taguchi, JoAnne Stubbe, Daniel G Nocera
Ribonucleotide reductases (RNR) catalyze the reduction of nucleotides to deoxynucleotides through a mechanism involving an essential cysteine based thiyl radical. In the E. coli class 1a RNR the thiyl radical (C439(•)) is a transient species generated by radical transfer (RT) from a stable diferric-tyrosyl radical cofactor located >35 Å away across the α2:β2 subunit interface. RT is facilitated by sequential proton-coupled electron transfer (PCET) steps along a pathway of redox active amino acids (Y122β ↔ [W48β?] ↔ Y356β ↔ Y731α ↔ Y730α ↔ C439α)...
November 9, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28979838/in%C3%A2-silico-analysis-of-heme-oxygenase-structural-homologues-identifies-group-specific-conservations
#14
Joseph Irvin, Alexander J Ropelewski, John Perozich
Heme oxygenases (HO) catalyze the breakdown of heme, aiding the recycling of its components. Several other enzymes have homologous tertiary structures to HOs, while sharing little sequence homology. These homologues include thiaminases, the hydroxylase component of methane monooxygenases, and the R2 component of Class I ribonucleotide reductases (RNR). This study compared these structural homologues of HO, using a large number of protein sequences for each homologue. Alignment of a total of 472 sequences showed little sequence conservation, with no residues having conservation in more than 80% of aligned sequences and only five residues conserved in at least 60% of the sequences...
October 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28978069/cell-cycle-perturbation-induced-by-gemcitabine-in-human-tumor-cells-in-cell-culture-xenografts-and-bladder-cancer-patients-implications-for-clinical-trial-designs-combining-gemcitabine-with-a-chk1-inhibitor
#15
Ryan Montano, Nadeem Khan, Huagang Hou, John Seigne, Marc S Ernstoff, Lionel D Lewis, Alan Eastman
Gemcitabine irreversibly inhibits ribonucleotide reductase and induces S phase arrest but whether this occurs in tumors in mice or patients has not been established. Tumor cells in culture were incubated with gemcitabine for 6 h to approximate the administration schedule in a patient. Concentrations that induced persistent S phase arrest thereafter correlated with cell killing. Administration of gemcitabine to mice also demonstrated a persistent S phase arrest in their tumor. The minimum dose that induced almost complete S phase arrest after 24 h (40 mg/kg) was well below the maximum tolerated dose in mice...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28972190/a-unique-cysteine-rich-zn-finger-domain-present-in-a-majority-of-class-ii-ribonucleotide-reductases-mediates-catalytic-turnover
#16
Christoph Loderer, Venkateswara Rao Jonna, Mikael Crona, Inna Rozman Grinberg, Margareta Sahlin, Anders Hofer, Daniel Lundin, Britt-Marie Sjöberg
Ribonucleotide reductases (RNRs) catalyze the reduction of ribonucleotides to the corresponding deoxyribonucleotides, used in DNA synthesis and repair. Two different mechanisms help deliver the required electrons to the RNR active site. Formate can be used as reductant directly in the active site, or gluta- or thioredoxins reduce a C-terminal cysteine pair, which then delivers the electrons to the active site. Here, we characterized a novel cysteine-rich C-terminal domain (CRD), which is present in most class II RNRs found in microbes...
October 2, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28964543/didox-3-4-dihydroxybenzohydroxamic-acid-suppresses-ige-mediated-mast-cell-activation-through-attenuation-of-nf%C3%AE%C2%BAb-and-ap-1-transcription
#17
Jamie Josephine Avila McLeod, Heather L Caslin, Andrew J Spence, Elizabeth M Kolawole, Amina Abdul Qayum, Anuya Paranjape, Marcela Taruselli, Tamara T Haque, Kasalina N Kiwanuka, Howard L Elford, John J Ryan
Mast cell activation via the high-affinity IgE receptor (FcεRI) elicits production of inflammatory mediators central to allergic disease. As a synthetic antioxidant and a potent ribonucleotide reductase (RNR) inhibitor, Didox (3,4-dihyroxybenzohydroxamic acid) has been tested in clinical trials for cancer and is an attractive therapeutic for inflammatory disease. We found that Didox treatment of mouse bone marrow-derived mast cells (BMMC) reduced IgE-stimulated degranulation and cytokine production, including IL-6, IL-13, TNF and MIP-1a (CCL3)...
September 21, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28928213/cell-cycle-inhibition-to-treat-sleeping-sickness
#18
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
#19
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
#20
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
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