Regulation of ribonucleotide reductase activity in mammalian cells

Cory, Joseph G.; Sato, Atsushi

doi:10.1007/978-1-4613-3879-6_16

Cited by 13 publications

(14 citation statements)

References 52 publications

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“…11). A similar sigmoid dependence of DNA synthesis on pools of four dNTPs has been previously demonstrated in cell culture (Cory et al, 1983(Cory et al, , 1986. The data shown in Figs.…”

Section: Metabolic Indicessupporting

confidence: 59%

“…Inhibition of dNTP synthesis by specific RDR inhibitors simultaneously decreased pools of four dNTPs and introduced DNA double-strand breaks and, eventually, caused cell death (Cory and Sato, 1983;Snyder, 1984;Cory and Carter, 1986;Hirota et al, 1989). One of the main factors of RDR suppression in the tissues of irradiated animals is radiation-induced inhibition of protein synthesis (Fig.…”

Section: Metabolic Indicesmentioning

confidence: 95%

“…The stage catalyzed by RDR requires permanent influx of four dNTPs for DNA synthesis and their concentration and proportions determine both the quality and rate of DNA synthesis. Even insignificant changes in dNTP pools or their disbalance induce deep inhibition of SHARYGIN et al DNA synthesis, which is due to the sigmoid dependencies of the rate of DNA synthesis and DNA polymerase activity on dNTP concentrations (Cory and Sato, 1983;Genetic Consequences… , 1985;Cory and Carter, 1986;Meuth, 1989;Hirota et al ., 1989;Pulatova et al ., 1989Pulatova et al ., , 1999. Radiation and many chemicals (most of which release nitric oxide during their transformation in the organism) inhibit RDR activity in hematopoietic organs, which considerably decreases dNTP pools.…”

Section: Introductionmentioning

confidence: 98%

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Activation of Deoxyribonucleotide Synthesis by Radioprotectants and Antioxidants as a Key Stage in Formation of Body Resistance to DNA-Damaging Factors

Sharygin

Pulatova

Shliakova

et al. 2005

Biol Bull Russ Acad Sci

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The responses of the systems of synthesis of deoxyribonucleotides (dNTPs), DNA, and proteins in hematopoietic organs and liver of animals to γ -radiation, administration of radioprotectants and antioxidants as well as the dependence of these responses on the doses of radiation and drugs were studied. Radioprotectants of acute (indralin) and durable effects (indomethaphen) as well as natural ( α 2 -tocopherol) and synthetic antioxidants (ionol or 2,6-di-tert-butyl-4-methylphenol) efficient in survival test were used. Three stages could be recognized in the standard unspecific response of the studied systems to radiation: (1) immediate increase in ribonucleotide reductase activity in the tissues within the first 30 min as a part of the integrated SOS response to DNA damage, which activates dNTP synthesis; (2) inhibition of the synthesis of dNTPs, DNA, and proteins; and (3) restoring ribonucleotide reductase activity and integral increase in the production of dNTPs, DNA, and total protein, which is essential for the development of compensatory and restorative responses of the organism. The radioprotectants significantly increased ribonucleotide reductase activity, which increased intracellular concentrations of the four dNTP types in organs during radiation exposure and three following days. Within this period, ribonucleotide reductase activity was inhibited by 40-50% in animals not treated with radioprotectants as compared to control. Balanced high pools of dNTPs in the organs of radioprotectant-treated animals provided for high-performance repair of DNA damage. The radioprotectant-induced activation of dNTP synthesis during the development of compensatory and restorative responses provides for an earlier restoration of the cellular composition and functioning of the organs. Antioxidants stimulated the synthesis of dNTPs, DNA, and proteins in animal tissues in a strict dose interval. Their effect on the studied syntheses was dose-dependent: single or multiple long-term administration of high antioxidant doses inhibited synthesis of dNTPs, DNA, and proteins. Radioprotectants and antioxidants affected the pool of blood protein Fe 3+ -transferrin controlling the synthesis of iron-containing ribonucleotide reductase activity in hematopoietic organs, and hence, the irondependent stage in DNA synthesis-dNTP synthesis. Activation of protein synthesis in organs by the studied substances increased the pools of Fe 3+ -transferrin and Cu 2+ -ceruloplasmin in the blood, which activated dNTP and DNA synthesis. Activated synthesis of dNTP, DNA, and proteins in the organs and increased pools of studied plasma proteins underlay the formation of body resistance to DNA-damaging factors. BIOCHEMISTRY * % of dogs and mice survived 45 and 30 days after irradiation, respectively. ** n , number of mice in a group.

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“…11). A similar sigmoid dependence of DNA synthesis on pools of four dNTPs has been previously demonstrated in cell culture (Cory et al, 1983(Cory et al, , 1986. The data shown in Figs.…”

Section: Metabolic Indicessupporting

confidence: 59%

Section: Metabolic Indicesmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 98%

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Activation of Deoxyribonucleotide Synthesis by Radioprotectants and Antioxidants as a Key Stage in Formation of Body Resistance to DNA-Damaging Factors

Sharygin

Pulatova

Shliakova

et al. 2005

Biol Bull Russ Acad Sci

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“…Therefore, the enzyme plays an important role in cell proliferation [54,55]. The effect of RR inactivation in cells includes decreases of intracellular concentrations of the dNTPs, inhibition of DNA synthesis, inhibition of DNA repair in quiescent cells, and cell cycle arrest and apoptosis [9,56].…”

Section: Ribonucleotide Reductase As a Target For Cancer Therapymentioning

confidence: 99%

Ribonucleotide Reductase Inhibitors and Future Drug Design

Shao¹,

Zhou²,

Chu³

et al. 2006

CCDT

251

249

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Ribonucleotide reductase (RR) is a multisubunit enzyme responsible for the reduction of ribonucleotides to their corresponding deoxyribonucleotides, which are building blocks for DNA replication and repair. The key role of RR in DNA synthesis and cell growth control has made it an important target for anticancer therapy. Increased RR activity has been associated with malignant transformation and tumor cell growth. Efforts for new RR inhibitors have been made in basic and translational research. In recent years, several RR inhibitors, including Triapine, Gemcitabine, and GTI-2040, have entered clinical trial or application. Furthermore, the discovery of p53R2, a p53-inducible form of the small subunit of RR, raises the interest to develop subunit-specific RR inhibitors for cancer treatment. This review compiles recent studies on (1) the structure, function, and regulation of two forms of RR; (2) the role in tumorigenesis of RR and the effect of RR inhibition in cancer treatment; (3) the classification, mechanisms of action, antitumor activity, and clinical trial and application of new RR inhibitors that have been used in clinical cancer chemotherapy or are being evaluated in clinical trials; (4) novel approaches for future RR inhibitor discovery.

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“…The two types of RR, i.e., RRM1-RRM2 and RRM1-RRM2B, provide dNTPs for DNA replication and repair, respectively [4,5]. RRM1 contains the catalytic site and allosteric regulation sites while RRM2 or RRM2B contains a diiron-tyrosyl radical cofactor required for the enzyme activity [6][7][8]. Since RR plays a vital role in DNA synthesis and cell proliferation, its expression and activity are tightly controlled in cells.…”

Section: Introductionmentioning

confidence: 99%

Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma

et al. 2015

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Ribonucleotide reductase (RR) has been reported to be associated with several types of cancer while the expression and role of RR in thyroid carcinoma (TC) has not been investigated. Here, we first examined the expression level of three RR subunit proteins (RRM1, RRM2, and RRM2B) in papillary thyroid carcinoma (PTC) and undifferentiated thyroid carcinoma (UTC) patient samples by immunohistochemistry. The results showed that RRM1 was higher expressed in 95.2 % cancer tissues compared with their adjacent normal tissues in 146 PTC samples. The expression level of RRM1 was positively correlated with T stage, lymph node metastasis (LNM), extrathyroidal invasion (ETI), and TNM stage in PTC patients. However, in 12 UTC samples, RRM1 expression was negatively expressed in six cases. To further determine the biological role of RRM1 in TC, ectopic expression or siRNA-mediated knockdown of RRM1 were carried out in the high-differentiated thyroid carcinoma cell line TPC-1 and the poor-differentiated thyroid carcinoma cell line SW579, respectively. In TPC-1 and SW579 cells, overexpression and siRNA knockdown of RRM1 demonstrated that RRM1 promoted DNA synthesis and proliferation in both cell lines as shown by EdU incorporation and cell viability assays. However, RRM1 enhanced cell migration and invasion in TPC-1 cells but inhibited that in SW579 cells as shown by wound healing and transwell assays. Moreover, we also found that RRM1 promoted PTEN expression and reduced Akt phosphorylation in a RR-activity-independent manner in the low-differentiated TC cells but not in the high-differentiated TC cells. In contrast, RRM2 expression was higher expressed in both PTC and UTC patient samples, consisting with its oncogenic role in other cancers. Therefore, we suggest that RRM1 promotes thyroid carcinoma proliferation as a component of RR but may play a different role in the invasion and metastasis of differently differentiated thyroid carcinomas through a non-RR pathway, which could be meaningful to precision treatment of thyroid carcinoma with RR inhibitors.

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Regulation of ribonucleotide reductase activity in mammalian cells

Cited by 13 publications

References 52 publications

Activation of Deoxyribonucleotide Synthesis by Radioprotectants and Antioxidants as a Key Stage in Formation of Body Resistance to DNA-Damaging Factors

Activation of Deoxyribonucleotide Synthesis by Radioprotectants and Antioxidants as a Key Stage in Formation of Body Resistance to DNA-Damaging Factors

Ribonucleotide Reductase Inhibitors and Future Drug Design

Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma

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