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Ribonucleotide reductase

Daniel C Anacker, Heather L Aloor, Caitlin N Shepard, Gina M Lenzi, Bryan A Johnson, Baek Kim, Cary A Moody
Productive replication of human papillomaviruses (HPV) is restricted to the uppermost layers of the differentiating epithelia. How HPV ensures an adequate supply of cellular substrates for viral DNA synthesis in a differentiating environment is unclear. Here, we demonstrate that HPV31 positive cells exhibit increased dNTP pools and levels of RRM2, a component of the ribonucleotide reductase (RNR) complex, which is required for de novo synthesis of dNTPs. RRM2 depletion blocks productive replication, suggesting RRM2 provides dNTPs for viral DNA synthesis in differentiating cells...
October 17, 2016: Virology
James J Farrell, Jennifer Moughan, Jonathan L Wong, William F Regine, Paul Schaefer, Al B Benson, John S Macdonald, Xiyong Liu, Yun Yen, Raymond Lai, Zhong Zheng, Gerold Bepler, Chandan Guha, Hany Elsaleh
OBJECTIVES: There is a need for validated predictive markers of gemcitabine response to guide precision medicine treatment in pancreatic cancer. We previously validated human equilibrative nucleoside transporter 1 as a predictive marker of gemcitabine treatment response using Radiation Therapy Oncology Group 9704. Controversy exists about the predictive value of gemcitabine metabolism pathway biomarkers: deoxycytidine kinase (DCK), ribonucleotide reductase 1 (RRM1), RRM2, and p53R2. METHODS: Radiation Therapy Oncology Group 9704 prospectively randomized 538 patients after pancreatic resection to receive either 5-fluorouracil or gemcitabine...
November 2016: Pancreas
Vince Kornél Grolmusz, Katalin Karászi, Tamás Micsik, Eszter Angéla Tóth, Katalin Mészáros, Gellért Karvaly, Gábor Barna, Péter Márton Szabó, Kornélia Baghy, János Matkó, Ilona Kovalszky, Miklós Tóth, Károly Rácz, Péter Igaz, Attila Patócs
Adrenocortical cancer (ACC) is a rare, but agressive malignancy with poor prognosis. Histopathological diagnosis is challenging and pharmacological options for treatment are limited. By the comparative reanalysis of the transcriptional malignancy signature with the cell cycle dependent transcriptional program of ACC, we aimed to identify novel biomarkers which may be used in the histopathological diagnosis and for the prediction of therapeutical response of ACC. Comparative reanalysis of publicly available microarray datasets included three earlier studies comparing transcriptional differences between ACC and benign adrenocortical adenoma (ACA) and one study presenting the cell cycle dependent gene expressional program of human ACC cell line NCI-H295R...
2016: American Journal of Cancer Research
Maryam Iman, Zeynab Khansepid, Asghar Davood
BACKGROUND: Ribonucleotide Reductase (RNR) is an important anticancer chemotherapy target. It has main key role in DNA synthesis and cell growth. Therefore several RNR inhibitors, such as Hydroxyurea, have entered the clinical trials. Based on our proposed mechanism, radical site of RNR protein reacts with Hydroxyurea in which hydroxyurea is converted into its oxidized form compound III, and whereby the tyrosyl radical is converted into a normal tyrosine residue. OBJECTIVE: In this study, docking and molecular dynamics simulations were used for proposed molecular mechanism of Hydroxyurea in RNR inhibition as anticancer agent...
September 26, 2016: Recent Patents on Anti-cancer Drug Discovery
Kanchana R Ravichandran, Alexander T Taguchi, Yifeng Wei, Cecilia Tommos, Daniel G Nocera, JoAnne Stubbe
Escherichia coli class Ia ribonucleotide reductase (RNR) converts ribonucleotides to deoxynucleotides. A diferric-tyrosyl radical (Y122•) in one subunit (β2) generates a transient thiyl radical in another subunit (α2) via long-range radical transport (RT) through aromatic amino acid residues (Y122 ⇆ [W48] ⇆ Y356 in β2 to Y731 ⇆ Y730 ⇆ C439 in α2). Equilibration of Y356•, Y731•, and Y730• was recently observed using site specifically incorporated unnatural tyrosine analogs; however, equilibration between Y122• and Y356• has not been detected...
October 7, 2016: Journal of the American Chemical Society
Andrew J Knappenberger, Md Faiz Ahmad, Rajesh Viswanathan, Chris G Dealwis, Michael E Harris
Class I ribonucleotide reductase (RR) maintains balanced pools of deoxyribonucleotide substrates for DNA replication by converting ribonucleoside diphosphates (NDPs) to 2'-deoxyribonucleoside diphosphates (dNDPs). Binding of deoxynucleoside triphosphate (dNTP) effectors (ATP/dATP, dGTP, and dTTP) modulates the specificity of class I RR for CDP, UDP, ADP, and GDP substrates. Crystal structures of bacterial and eukaryotic RRs show that dNTP effectors and NDP substrates bind on either side of a flexible nine-amino acid loop (loop 2)...
October 3, 2016: Biochemistry
Sam L Teichman, Kassandra S Thomson, Michael Regnier
Chronic inotropic therapy is effective for the treatment of heart failure with reduced ejection fraction, but has been limited by adverse long-term safety profiles, development of tolerance, and the need for chronic parenteral administration. A safe and convenient therapeutic agent that produces sustained inotropic effects could improve symptoms, functional capacity, and quality of life. Small amounts of 2-deoxy-adenosine triphosphate (dATP) activate cardiac myosin leading to enhanced contractility in normal and failing heart muscle...
September 3, 2016: Handbook of Experimental Pharmacology
Shin Yup Lee, Hyo-Gyoung Kang, Jin Eun Choi, Deuk Kju Jung, Won Kee Lee, Hyun Chul Lee, So Yeon Lee, Seung Soo Yoo, Jaehee Lee, Yangki Seok, Eung Bae Lee, Seung Ick Cha, Sukki Cho, Chang Ho Kim, Myung Hoon Lee, Jae Yong Park
We evaluated the associations between potentially functional variants in a comprehensive list of cancer-related genes and lung cancer in a Korean population.A total of 1969 potentially functional single nucleotide polymorphisms (SNPs) of 1151 genes involved in carcinogenesis were evaluated using an Affymetrix custom-made GeneChip in 610 nonsmall cell lung cancer patients and 610 healthy controls. A replication study was conducted in an independent set of 490 cases and 486 controls. 68 SNPs were significantly associated with lung cancer in the discovery set and tested for replication...
October 2016: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
Yong-Jie Xu, Amanpreet Singh, Gerald M Alter
Hydroxyurea (HU) has been used for the treatment of multiple diseases such as cancer. The therapeutic effect is generally believed to be due to the suppression of ribonucleotide reductase, which slows DNA polymerase movement at replication forks and induces an S phase cell cycle arrest in proliferating cells. Although aberrant mitosis and DNA damage generated at collapsed forks are the likely causes of cell death in the mutants with defects in replication stress response, the mechanism underlying the cytotoxicity of HU in wild type cells remains poorly understood...
August 31, 2016: Genetics
Bong Gyun Kim, Hong Woo Park
Adaptation of dihydrofolate reductase (DHFR)-deficient Chinese hamster ovary (CHO) DG44 cells to chemically defined suspension culture conditions is a time-consuming and labor-intensive process because non-adapted DHFR-deficient CHO DG44 cells normally show poor growth in chemically defined medium (CDM). We examined the effects of folate derivatives, ribonucleotides, and nucleobases on the growth of suspension-adapted DHFR-deficient CHO DG44 cells in CDM. Among the tested additives, tetrahydrofolate (THF) was identified as an effective component for increasing cell growth...
August 31, 2016: Biotechnology Progress
Emre Murat Altinkilic, Selim Isbir, Uzay Gormus, Seda Gulec Yilmaz, Altay Burak Dalan, Selvi Duman, Turgay Isbir
BACKGROUND/AIM: Coronary artery disease (CAD) is a chronic inflammatory disease seen as formation of atherosclerotic plaques (atheroma) in coronary arteries. Recent published papers show that DNA damage and repair mechanisms play a crucial role on the development and severity of atheromas. In this study, we investigated nucleotide excision repair (NER) pathway-related gene polymorphisms in atherosclerosis. XPD, encoded by ERCC2 gene, is an ATP-depended helicase enzyme involved in the NER pathway...
September 2016: In Vivo
Marie Lofstad, Ingvild Gudim, Marta Hammerstad, Åsmund Kjendseth Røhr, Hans-Petter Hersleth
To reduce ribonucleotides to deoxyribonucleotides, the manganese-bound form of class Ib ribonucleotide reductase (RNR) must be activated via a pathway that involves redox protein(s). The reduced flavoprotein NrdI is an important protein in this pathway, as it reduces dioxygen to superoxide. Superoxide then reacts with the RNR Mn(II)2 site to generate a tyrosyl radical that is required for catalysis. A native NrdI reductase has not yet been identified. We herein demonstrate through kinetic and spectroscopic studies that an endogenous flavodoxin reductase can function as the NrdI reductase in Bacillus cereus...
September 13, 2016: Biochemistry
Kelli L Goss, David J Gordon
There is a critical need in cancer therapeutics to identify targeted therapies that will improve outcomes and decrease toxicities compared to conventional, cytotoxic chemotherapy. Ewing sarcoma is a highly aggressive bone and soft tissue cancer that is caused by the EWS-FLI1 fusion protein. Although EWS-FLI1 is specific for cancer cells, and required for tumorigenesis, directly targeting this transcription factor has proven challenging. Consequently, targeting unique dependencies or key downstream mediators of EWS-FLI1 represent important alternative strategies...
August 19, 2016: Oncotarget
Y-Y Hsieh, C-J Chou, H-L Lo, P-M Yang
Colorectal cancer (CRC) is the second leading cause of cancer-related death in males and females in the world. It is of immediate importance to develop novel therapeutics. Human ribonucleotide reductase (RRM1/RRM2) has an essential role in converting ribonucleoside diphosphate to 2'-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools. RRM2 is a prognostic biomarker and predicts poor survival of CRC. In addition, increased RRM2 activity is associated with malignant transformation and tumor cell growth...
2016: Cell Death Discovery
Zhe Yang, Honghai Dai, Dongxiao Lv, A Lei Feng, Weibin Shu, Junqing Han
OBJECTIVE: To make an informed choice of chemotherapy drugs according to the oncogene mRNA expression and to explore whether it could increase the survival rate of patients. PATIENTS AND METHODS: The study retrospectively analyzed 36 cases of nonsurgical esophageal squamous cell carcinoma patients treated at the Center for Oncology of Shandong Provincial Hospital from December 1, 2010, to November 1, 2013. Intensity-modulated radiation therapy was used for the treatment with a conventional radiotherapy dose of 60-66 Gy...
2016: OncoTargets and Therapy
Clayton S Lewis, Christina Voelkel-Johnson, Charles D Smith
Pancreatic cancer remains extremely difficult to treat, with the average lifespan following diagnosis being only 3-6 months, resulting in a death to incidence ratio of 0.94. A major reason for this high mortality rate is resistance to the main chemotherapeutic agent used to treat this disease, gemcitabine. Alterations in nucleoside and gemcitabine metabolism, specifically over-expression of ribonucleotide reductase, have been implicated as a major mechanism of resistance to this drug. Here, we show that inhibition of sphingosine kinase-2 by the specific inhibitor ABC294640 is synergistically cytotoxic with gemcitabine toward three human pancreatic cancer cell lines...
August 8, 2016: Oncotarget
Mikael Crona, Paula Codó, Venkateswara Rao Jonna, Anders Hofer, Aristi P Fernandes, Fredrik Tholander
Ribonucleotide Reductase (RNR) is the sole enzyme that catalyzes the reduction of ribonucleotides into deoxyribonucleotides. Even though RNR is a recognized target for antiproliferative molecules, and the main target of the approved drug hydroxyurea, few new leads targeted to this enzyme have been developed. We have evaluated a recently identified set of RNR inhibitors with respect to inhibition of the human enzyme and cellular toxicity. One compound, NSC73735, is particularly interesting; it is specific for leukemia cells and is the first identified compound that hinders oligomerization of the mammalian large RNR subunit...
November 2016: Molecular Oncology
Maria Pujantell, Roger Badia, Cristina Ramirez, Teresa Puig, Bonaventura Clotet, Ester Ballana, José A Esté, Eva Riveira-Muñoz
HIV-1 infection is thought to impair type I interferon (IFN-I) production in macrophages, a cell type that is also relatively resistant to HIV-1 cytotoxic effects. Here, we show that monocyte differentiation into macrophages by M-CSF led to cell proliferation and susceptibility to HIV-1 infection that induced cell cycle arrest and increased cell death. Established HIV-1 infection of monocyte-derived macrophages induced the upregulation of the pattern recognition receptors MDA5 and Rig-I that serve as virus sensors; production of interferon-β, and transcription of interferon-stimulated genes including CXCL10...
September 2016: Antiviral Research
Renzo Johansson, Venkateswara Rao Jonna, Rohit Kumar, Niloofar Nayeri, Daniel Lundin, Britt-Marie Sjöberg, Anders Hofer, Derek T Logan
No abstract text is available yet for this article.
August 2, 2016: Structure
Chih-Wei Chen, Ning Tsao, Lin-Yi Huang, Yun Yen, Xiyong Liu, Christine Lehman, Yuh-Hwa Wang, Mei-Chun Tseng, Yu-Ju Chen, Yi-Chi Ho, Chian-Feng Chen, Zee-Fen Chang
The appropriate supply of dNTPs is critical for cell growth and genome integrity. Here, we investigated the interrelationship between dUTP pyrophosphatase (dUTPase) and ribonucleotide reductase (RNR) in the regulation of genome stability. Our results demonstrate that reducing the expression of dUTPase increases genome stress in cancer. Analysis of clinical samples reveals a significant correlation between the combination of low dUTPase and high R2, a subunit of RNR, and a poor prognosis in colorectal and breast cancer patients...
August 2, 2016: Cell Reports
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