Ribonucleotide Reductases

Division of Biophysics and 2Division of Biochemistry, Medical Nobel Institute, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden.
Annual Review of Biochemistry (Impact Factor: 30.28). 02/2006; 75(1):681-706. DOI: 10.1146/annurev.biochem.75.103004.142443
Source: PubMed


Ribonucleotide reductases (RNRs) transform RNA building blocks to DNA building blocks by catalyzing the substitution of the 2'OH-group of a ribonucleotide with a hydrogen by a mechanism involving protein radicals. Three classes of RNRs employ different mechanisms for the generation of the protein radical. Recent structural studies of members from each class have led to a deeper understanding of their catalytic mechanism and allosteric regulation by nucleoside triphosphates. The main emphasis of this review is on regulation of RNR at the molecular and cellular level. Conformational transitions induced by nucleotide binding determine the regulation of substrate specificity. An intricate interplay between gene activation, enzyme inhibition, and protein degradation regulates, together with the allosteric effects, enzyme activity and provides the appropriate amount of deoxynucleotides for DNA replication and repair. In spite of large differences in the amino acid sequences, basic structural features are remarkably similar and suggest a common evolutionary origin for the three classes.

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    • "Initial grouping of DE genes into predicted functional categories showed H 2 O 2 exposure triggered up-regulation of genes involved in several such systems in both strains (Table 2). Examples include several genes involved in the thioredoxin reductase system which, under favorable growth conditions, functions with ribonucleoside reductase to use NADPH to reduce the 2 OH group of ribose for deoxynucleotide production, as well as to maintain cytoplasmic redox for disulfide bond production in proteins (Nordlund and Reichard, 2006; Arnér and Holmgren, 2001). During oxidative stress; however, cells may use thioredoxin reductase and peroxiredoxin to direct NADPH toward the removal of oxidative free radicals via the reduction of H 2 O 2 and toxic lipid hydroperoxides (Reott et al., 2009; Meyer et al., 2009; Holmgren, 1989). "
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    ABSTRACT: Consumer and commercial interest in foods containing probiotic bifidobacteria is increasing. However, because bifidobacteria are anaerobic, oxidative stress can diminish cell viability during production and storage of bioactive foods. We previously found Bifidobacterium longum strain NCC2705 had significantly greater intrinsic and inducible resistance to hydrogen peroxide (H2O2) than strain D2957. Here, we explored the basis for these differences by examining the transcriptional responses of both strains to sub-lethal H2O2 exposure for 5- or 60- min. Strain NCC2705 had 288 genes that were differentially expressed after the 5-min treatment and 114 differentially expressed genes after the 60-min treatment. In contrast, strain D2957 had only 21 and 90 differentially expressed genes after the 5-and 60-min treatments, respectively. Both strains showed up-regulation of genes coding enzymes implicated in oxidative stress resistance, such as thioredoxin, thioredoxin reductase, peroxiredoxin, ferredoxin, glutaredoxin, and anaerobic ribonucleotide reductase, but induction levels were typically highest in NCC2705. Compared to D2957, NCC2705 also had more up-regulated genes involved in transcriptional regulation and more down-regulated genes involved in sugar transport and metabolism. These results provide a greater understanding of the molecular basis for oxidative stress resistance in B. longum and the factors that contribute to strain-to-strain variability in survival in bioactive food products. Copyright © 2015. Published by Elsevier B.V.
    Journal of Biotechnology 08/2015; 212. DOI:10.1016/j.jbiotec.2015.06.405 · 2.87 Impact Factor
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    • "RRM1 contains a catalytic site and two allosteric effector-binding sites. RRM2 and RRM2B contain a diiron-tyrosyl radical required for the enzyme activity [6]. The RR holoenzyme constitutes two forms: RRM1- RRM2 and RRM1-RRM2B which provide dNTP for DNA replication and repair, respectively [7]. "
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    ABSTRACT: As the ribonucleotide reductase small subunit, the high expression of ribonucleotide reductase small subunit M2 (RRM2) induces cancer and contributes to tumor growth and invasion. In several colorectal cancer (CRC) cell lines, we found that the expression levels of RRM2 were closely related to the transcription factor E2F1. Mechanistic studies were conducted to determine the molecular basis. Ectopic overexpression of E2F1 promoted RRM2 transactivation while knockdown of E2F1 reduced the levels of RRM2 mRNA and protein. To further investigate the roles of RRM2 which was activated by E2F1 in CRC, CCK-8 assay and EdU incorporation assay were performed. Overexpression of E2F1 promoted cell proliferation in CRC cells, which was blocked by RRM2 knockdown attenuation. In the migration and invasion tests, overexpression of E2F1 enhanced the migration and invasion of CRC cells which was abrogated by silencing RRM2. Besides, overexpression of RRM2 reversed the effects of E2F1 knockdown partially in CRC cells. Examination of clinical CRC specimens demonstrated that both RRM2 and E2F1 were elevated in most cancer tissues compared to the paired normal tissues. Further analysis showed that the protein expression levels of E2F1 and RRM2 were parallel with each other and positively correlated with lymph node metastasis (LNM), TNM stage and distant metastasis. Consistently, the patients with low E2F1 and RRM2 levels have a better prognosis than those with high levels. Therefore, we suggest that E2F1 can promote CRC proliferation, migration, invasion and metastasis by regulating RRM2 transactivation. Understanding the role of E2F1 in activating RRM2 transcription will help to explain the relationship between E2F1 and RRM2 in CRC and provide a novel predictive marker for diagnosis and prognosis of the disease. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 06/2015; 464(2). DOI:10.1016/j.bbrc.2015.06.103 · 2.30 Impact Factor
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    • "Ribonucleotide reductase (RNR) is involved in de novo dNTP synthesis (Figure S3A) (Nordlund and Reichard, 2006; Reichard, 1988). We first sought to determine whether the increase in dNTPs was due to the salvage pathway, which does not rely on RNR (Blakley and Vitols, 1968; Murray, 1971; Reichard, 1988). "
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    ABSTRACT: Replication stress induced by nucleotide deficiency plays an important role in cancer initiation. Replication stress in primary cells typically activates the cellular senescence tumor-suppression mechanism. Senescence bypass correlates with development of cancer, a disease characterized by metabolic reprogramming. However, the role of metabolic reprogramming in the cellular response to replication stress has been little explored. Here, we report that ataxia telangiectasia mutated (ATM) plays a central role in regulating the cellular response to replication stress by shifting cellular metabolism. ATM inactivation bypasses senescence induced by replication stress triggered by nucleotide deficiency. This was due to restoration of deoxyribonucleotide triphosphate (dNTP) levels through both upregulation of the pentose phosphate pathway via increased glucose-6-phosphate dehydrogenase (G6PD) activity and enhanced glucose and glutamine consumption. These phenotypes were mediated by a coordinated suppression of p53 and upregulation of c-MYC downstream of ATM inactivation. Our data indicate that ATM status couples replication stress and metabolic reprogramming during senescence. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(6). DOI:10.1016/j.celrep.2015.04.014 · 8.36 Impact Factor
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