Ribonucleotide reductase metallocofactor: assembly, maintenance and inhibition

Abstract

Ribonucleotide reductase (RNR) supplies cellular deoxyribonucleotide triphosphates (dNTP) pools by converting ribonucleotides to the corresponding deoxy forms using radical-based chemistry. Eukaryotic RNR comprises α and β subunits: α contains the catalytic and allosteric sites; β houses a diferric-tyrosyl radical cofactor (Fe^III₂-Y•) that is required to initiates nucleotide reduction in α. Cells have evolved multi-layered mechanisms to regulate RNR level and activity in order to maintain the adequate sizes and ratios of their dNTP pools to ensure high-fidelity DNA replication and repair. The central role of RNR in nucleotide metabolism also makes it a proven target of chemotherapeutics. In this review, we discuss recent progress in understanding the function and regulation of eukaryotic RNRs, with a focus on studies revealing the cellular machineries involved in RNR metallocofactor biosynthesis and its implication in RNR-targeting therapeutics.

Keywords

ribonucleotide reductase (RNR) / diferric-tyrosyl radical (Fe^III₂-Y•) / iron homeostasis

References

[1] AllenJ B, ZhouZ, SiedeW, FriedbergE C, ElledgeS J (1994). The SAD1/RAD53 protein kinase controls multiple checkpoints and DNA damage-induced transcription in yeast. Genes Dev, 8(20): 2401–2415

[2] AtkinC L, ThelanderL, ReichardP, LangG (1973). Iron and free radical in ribonucleotide reductase. Exchange of iron and Mössbauer spectroscopy of the protein B2 subunit of the Escherichia coli enzyme. J Biol Chem, 248(21): 7464–7472

[3] AyeY, BrignoleE J, LongM J, ChittuluruJ, DrennanC L, AsturiasF J, StubbeJ (2012a). Clofarabine targets the large subunit (α) of human ribonucleotide reductase in live cells by assembly into persistent hexamers. Chem Biol, 19(7): 799–805

[4] AyeY, LongM J, StubbeJ (2012b). Mechanistic studies of semicarbazone triapine targeting human ribonucleotide reductase in vitro and in mammalian cells: tyrosyl radical quenching not involving reactive oxygen species. J Biol Chem, 287(42): 35768–35778

[5] BarlowT, EliassonR, PlatzA, ReichardP, SjöbergB M (1983). Enzymic modification of a tyrosine residue to a stable free radical in ribonucleotide reductase. Proc Natl Acad Sci USA, 80(6): 1492–1495

[6] BianchiV, PontisE, ReichardP (1986). Changes of deoxyribonucleoside triphosphate pools induced by hydroxyurea and their relation to DNA synthesis. J Biol Chem, 261(34): 16037–16042

[7] BjörklundS, SkogS, TribukaitB, ThelanderL (1990). S-phase-specific expression of mammalian ribonucleotide reductase R1 and R2 subunit mRNAs. Biochemistry, 29(23): 5452–5458

[8] BoehmerP E, LehmanI R (1997). Herpes simplex virus DNA replication. Annu Rev Biochem, 66(1): 347–384

[9] BollingerJ M Jr, EdmondsonD E, HuynhB H, FilleyJ, NortonJ R, StubbeJ (1991). Mechanism of assembly of the tyrosyl radical-dinuclear iron cluster cofactor of ribonucleotide reductase. Science, 253(5017): 292–298

[10] BollingerJ M Jr, JiangW, GreenM T, KrebsC (2008). The manganese(IV)/iron(III) cofactor of Chlamydia trachomatis ribonucleotide reductase: structure, assembly, radical initiation, and evolution. Curr Opin Struct Biol, 18(6): 650–657

[11] BollingerJ M Jr, TongW H, RaviN, HuynhB H, EdmondsonD E, StubbeJ A (1995). Use of rapid kinetics methods to study the assembly of the diferric-tyrosyl radical cofactor of E. coli ribonucleotide reductase. Methods Enzymol, 258: 278–303

[12] BrockmanR W, ShaddixS, LasterW R Jr, SchabelF M Jr (1970). Inhibition of ribonucleotide reductase, DNA synthesis, and L1210 leukemia by guanazole. Cancer Res, 30(9): 2358–2368

[13] BurrellR A, McClellandS E, EndesfelderD, GrothP, WellerM C, ShaikhN, DomingoE, KanuN, DewhurstS M, GronroosE, ChewS K, RowanA J, SchenkA, ShefferM, HowellM, KschischoM, BehrensA, HelledayT, BartekJ, TomlinsonI P, SwantonC (2013). Replication stress links structural and numerical cancer chromosomal instability. Nature, 494(7438): 492–496

[14] BussJ L, TortiF M, TortiS V (2003). The role of iron chelation in cancer therapy. Curr Med Chem, 10(12): 1021–1034

[15] CairnsR A, HarrisI S, MakT W (2011). Regulation of cancer cell metabolism. Nat Rev Cancer, 11(2): 85–95

[16] CampestreC, AgamennoneM, TortorellaP, PreziusoS, BiasoneA, GavuzzoE, PochettiG, MazzaF, HillerO, TschescheH, ConsalviV, GallinaC (2006). N-Hydroxyurea as zinc binding group in matrix metalloproteinase inhibition: mode of binding in a complex with MMP-8. Bioorg Med Chem Lett, 16(1): 20–24

[17] CerqueiraN M, FernandesP A, RamosM J (2007). Ribonucleotide reductase: a critical enzyme for cancer chemotherapy and antiviral agents. Recent Patents Anticancer Drug Discov, 2(1): 11–29

[18] ChabesA, GeorgievaB, DomkinV, ZhaoX, RothsteinR, ThelanderL (2003a). Survival of DNA damage in yeast directly depends on increased dNTP levels allowed by relaxed feedback inhibition of ribonucleotide reductase. Cell, 112(3): 391–401

[19] ChabesA, ThelanderL (2003). DNA building blocks at the foundation of better survival. Cell Cycle, 2(3): 171–173

[20] ChabesA L, PflegerC M, KirschnerM W, ThelanderL (2003b). Mouse ribonucleotide reductase R2 protein: a new target for anaphase-promoting complex-Cdh1-mediated proteolysis. Proc Natl Acad Sci USA, 100(7): 3925–3929

[21] ChaboutéM E, ClémentB, PhilippsG (2002). S phase and meristem-specific expression of the tobacco RNR1b gene is mediated by an E2F element located in the 5′ leader sequence. J Biol Chem, 277(20): 17845–17851

[22] ChaboutéM E, ClémentB, SekineM, PhilippsG, Chaubet-GigotN (2000). Cell cycle regulation of the tobacco ribonucleotide reductase small subunit gene is mediated by E2F-like elements. Plant Cell, 12(10): 1987–2000

[23] ChastonT B, LovejoyD B, WattsR N, RichardsonD R (2003). Examination of the antiproliferative activity of iron chelators: multiple cellular targets and the different mechanism of action of triapine compared with desferrioxamine and the potent pyridoxal isonicotinoyl hydrazone analogue 311. Clin Cancer Res, 9(1): 402–414

[24] ChastonT B, RichardsonD R (2003). Iron chelators for the treatment of iron overload disease: relationship between structure, redox activity, and toxicity. Am J Hematol, 73(3): 200–210

[25] ClimentI, SjöbergB M, HuangC Y (1991). Carboxyl-terminal peptides as probes for Escherichia coli ribonucleotide reductase subunit interaction: kinetic analysis of inhibition studies. Biochemistry, 30(21): 5164–5171

[26] CotruvoJ A Jr, StubbeJ (2010). An active dimanganese(III)-tyrosyl radical cofactor in Escherichia coli class Ib ribonucleotide reductase. Biochemistry, 49(6): 1297–1309

[27] CotruvoJ A Jr, StubbeJ (2011). Class I ribonucleotide reductases: metallocofactor assembly and repair in vitro and in vivo. Annu Rev Biochem, 80(1): 733–767

[28] CovesJ, ZeghoufM, MacherelD, GuigliarelliB, AssoM, FontecaveM (1997). Flavin mononucleotide-binding domain of the flavoprotein component of the sulfite reductase from Escherichia coli. Biochemistry, 36(19): 5921–5928

[29] D’AngiolellaV, DonatoV, ForresterF M, JeongY T, PellacaniC, KudoY, SarafA, FlorensL, WashburnM P, PaganoM (2012). Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair. Cell, 149(5): 1023–1034

[30] DaviesB W, KohanskiM A, SimmonsL A, WinklerJ A, CollinsJ J, WalkerG C (2009). Hydroxyurea induces hydroxyl radical-mediated cell death in Escherichia coli. Mol Cell, 36(5): 845–860

[31] DayaniP N, BishopM C, BlackK, ZeltzerP M (2004). Desferoxamine (DFO)—mediated iron chelation: rationale for a novel approach to therapy for brain cancer. J Neurooncol, 67(3): 367–377

[32] DonehowerR C (1992). An overview of the clinical experience with hydroxyurea. Semin Oncol, 19(3 Suppl 9): 11–19

[33] EklundH, UhlinU, FärnegårdhM, LoganD T, NordlundP (2001). Structure and function of the radical enzyme ribonucleotide reductase. Prog Biophys Mol Biol, 77(3): 177–268

[34] ElledgeS J, ZhouZ, AllenJ B, NavasT A (1993). DNA damage and cell cycle regulation of ribonucleotide reductase. BioEssays, 15: 333–339

[35] EnyedyE A, PrimikM F, KowolC R, ArionV B, KissT, KepplerB K (2011). Interaction of Triapine and related thiosemicarbazones with iron(III)/(II) and gallium(III): a comparative solution equilibrium study. Dalton Trans, 40(22): 5895–5905

[36] FanH, VillegasC, HuangA, WrightJ A (1998). The mammalian ribonucleotide reductase R2 component cooperates with a variety of oncogenes in mechanisms of cellular transformation. Cancer Res, 58(8): 1650–1653

[37] FinchR A, LiuM C, CoryA H, CoryJ G, SartorelliA C (1999). Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP): an inhibitor of ribonucleotide reductase with antineoplastic activity. Adv Enzyme Regul, 39(1): 3–12

[38] FishbeinW N, CarboneP P (1963). Hydroxyurea: Mechanism of Action. Science, 142(3595): 1069–1070

[39] FontecaveM, EliassonR, ReichardP (1987). NAD(P)H:flavin oxidoreductase of Escherichia coli. A ferric iron reductase participating in the generation of the free radical of ribonucleotide reductase. J Biol Chem, 262(25): 12325–12331

[40] FontecaveM, EliassonR, ReichardP (1989). Enzymatic regulation of the radical content of the small subunit of Escherichia coli ribonucleotide reductase involving reduction of its redox centers. J Biol Chem, 264(16): 9164–9170

[41] FontecaveM, MulliezE, LoganD T (2002). Deoxyribonucleotide synthesis in anaerobic microorganisms: the class III ribonucleotide reductase. Prog Nucleic Acid Res Mol Biol, 72: 95–127

[42] GwiltP R, TracewellW G (1998). Pharmacokinetics and pharmacodynamics of hydroxyurea. Clin Pharmacokinet, 34(5): 347–358

[43] HalimiY, DessauM, PollakS, AstT, ErezT, Livnat-LevanonN, KarniolB, HirschJ A, ChamovitzD A (2011). COP9 signalosome subunit 7 from Arabidopsis interacts with and regulates the small subunit of ribonucleotide reductase (RNR2). Plant Mol Biol, 77(1-2): 77–89

[44] HanahanD, WeinbergR A (2011). Hallmarks of cancer: the next generation. Cell, 144(5): 646–674

[45] HaoZ, QiaoT, JinX, LiX, GaoJ, FanD (2005). Preparation and characterization of a specific monoclonal antibody against CIAPIN1. Hybridoma (Larchmt), 24(3): 141–145

[46] HarperJ W, ElledgeS J (2007). The DNA damage response: ten years after. Mol Cell, 28(5): 739–745

[47] HaunhorstP, HanschmannE M, BräutigamL, StehlingO, HoffmannB, MühlenhoffU, LillR, BerndtC, LilligC H (2013). Crucial function of vertebrate glutaredoxin 3 (PICOT) in iron homeostasis and hemoglobin maturation. Mol Biol Cell, 24(12): 1895–1903

[48] HoferA, CronaM, LoganD T, SjöbergB M (2012). DNA building blocks: keeping control of manufacture. Crit Rev Biochem Mol Biol, 47(1): 50–63

[49] HristovaD, WuC H, JiangW, KrebsC, StubbeJ (2008). Importance of the maintenance pathway in the regulation of the activity of Escherichia coli ribonucleotide reductase. Biochemistry, 47(13): 3989–3999

[50] HuC M, YehM T, TsaoN, ChenC W, GaoQ Z, ChangC Y, LeeM H, FangJ M, SheuS Y, LinC J, TsengM C, ChenY J, ChangZ F (2012). Tumor cells require thymidylate kinase to prevent dUTP incorporation during DNA repair. Cancer Cell, 22(1): 36–50

[51] HuangM, ElledgeS J (1997). Identification of RNR4, encoding a second essential small subunit of ribonucleotide reductase in Saccharomyces cerevisiae. Mol Cell Biol, 17(10): 6105–6113

[52] JiangW, YunD, SalehL, BarrE W, XingG, HoffartL M, MaslakM A, KrebsC, BollingerJ M Jr (2007). A manganese(IV)/iron(III) cofactor in Chlamydia trachomatis ribonucleotide reductase. Science, 316(5828): 1188–1191

[53] JohnsD G, GaoW Y (1998). Selective depletion of DNA precursors: an evolving strategy for potentiation of dideoxynucleoside activity against human immunodeficiency virus. Biochem Pharmacol, 55(10): 1551–1556

[54] JordanA, ReichardP (1998). Ribonucleotide reductases. Annu Rev Biochem, 67(1): 71–98

[55] KaplanJ, McVey WardD, CrispR J, PhilpottC C (2006). Iron-dependent metabolic remodeling in S. cerevisiae. Biochim Biophys Acta, 1763(7): 646–651

[56] KashlanO B, CoopermanB S (2003). Comprehensive model for allosteric regulation of mammalian ribonucleotide reductase: refinements and consequences. Biochemistry, 42(6): 1696–1706

[57] KeP Y, KuoY Y, HuC M, ChangZ F (2005). Control of dTTP pool size by anaphase promoting complex/cyclosome is essential for the maintenance of genetic stability. Genes Dev, 19(16): 1920–1933

[58] KennedyB J (1992). The evolution of hydroxyurea therapy in chronic myelogenous leukemia. Semin Oncol, 19(3 Suppl 9): 21–26

[59] KolbergM, StrandK R, GraffP, AnderssonK K (2004). Structure, function, and mechanism of ribonucleotide reductases. Biochim Biophys Acta, 1699(1-2): 1–34

[60] KumarD, VibergJ, NilssonA K, ChabesA (2010). Highly mutagenic and severely imbalanced dNTP pools can escape detection by the S-phase checkpoint. Nucleic Acids Res, 38(12): 3975–3983

[61] KunkelT A, SilberJ R, LoebL A (1982). The mutagenic effect of deoxynucleotide substrate imbalances during DNA synthesis with mammalian DNA polymerases. Mutat Res, 94(2): 413–419

[62] KunosC, RadivoyevitchT, Abdul-KarimF W, FanningJ, AbulafiaO, BonebrakeA J, UshaL (2012). Ribonucleotide reductase inhibition restores platinum-sensitivity in platinum-resistant ovarian cancer: a Gynecologic Oncology Group Study. J Transl Med, 10(1): 79

[63] KuritaJ, NakajimaK (2012). Megalocytiviruses. Viruses, 4(4): 521–538

[64] LassmannG, ThelanderL, GräslundA (1992). EPR stopped-flow studies of the reaction of the tyrosyl radical of protein R2 from ribonucleotide reductase with hydroxyurea. Biochem Biophys Res Commun, 188(2): 879–887

[65] LeeY D, WangJ, StubbeJ, ElledgeS J (2008). Dif1 is a DNA-damage-regulated facilitator of nuclear import for ribonucleotide reductase. Mol Cell, 32(1): 70–80

[66] LillR, HoffmannB, MolikS, PierikA J, RietzschelN, StehlingO, UzarskaM A, WebertH, WilbrechtC, MühlenhoffU (2012). The role of mitochondria in cellular iron-sulfur protein biogenesis and iron metabolism. Biochim Biophys Acta, 1823(9): 1491–1508

[67] LiuC, PowellK A, MundtK, WuL, CarrA M, CaspariT (2003). Cop9/signalosome subunits and Pcu4 regulate ribonucleotide reductase by both checkpoint-dependent and-independent mechanisms. Genes Dev, 17(9): 1130–1140

[68] LiuX, ZhouB, XueL, YenF, ChuP, UnF, YenY (2007). Ribonucleotide reductase subunits M2 and p53R2 are potential biomarkers for metastasis of colon cancer. Clin Colorectal Cancer, 6(5): 374–381

[69] LoebL A, KunkelT A (1982). Fidelity of DNA synthesis. Annu Rev Biochem, 51(1): 429–457

[70] LoganD T, MulliezE, LarssonK M, BodevinS, AttaM, GarnaudP E, SjobergB M, FontecaveM (2003). A metal-binding site in the catalytic subunit of anaerobic ribonucleotide reductase. Proc Natl Acad Sci USA, 100(7): 3826–3831

[71] LovejoyD B, RichardsonD R (2003). Iron chelators as anti-neoplastic agents: current developments and promise of the PIH class of chelators. Curr Med Chem, 10(12): 1035–1049

[72] MadaanK, KaushikD, VermaT (2012). Hydroxyurea: a key player in cancer chemotherapy. Expert Rev Anticancer Ther, 12(1): 19–29

[73] MathewsC K (2006). DNA precursor metabolism and genomic stability. FASEB J, 20: 1300–1314

[74] MayhewC N, SumpterR, InayatM, CibullM, PhillipsJ D, ElfordH L, GallicchioV S (2005). Combination of inhibitors of lymphocyte activation (hydroxyurea, trimidox, and didox) and reverse transcriptase (didanosine) suppresses development of murine retrovirus-induced lymphoproliferative disease. Antiviral Res, 65(1): 13–22

[75] MinnihanE C, AndoN, BrignoleE J, OlshanskyL, ChittuluruJ, AsturiasF J, DrennanC L, NoceraD G, StubbeJ (2013a). Generation of a stable, aminotyrosyl radical-induced α2β2 complex of Escherichia coli class Ia ribonucleotide reductase. Proc Natl Acad Sci USA, 110(10): 3835–3840

[76] MinnihanE C, NoceraD G, StubbeJ (2013b). Reversible, long-range radical transfer in E. coli class Ia ribonucleotide reductase. Acc Chem Res, 46(11): 2524–2535

[77] MiyajimaH, TakahashiY, KamataT, ShimizuH, SakaiN, GitlinJ D (1997). Use of desferrioxamine in the treatment of aceruloplasminemia. Ann Neurol, 41(3): 404–407

[78] MowaM B, WarnerD F, KaplanG, KanaB D, MizrahiV (2009). Function and regulation of class I ribonucleotide reductase-encoding genes in mycobacteria. J Bacteriol, 191(3): 985–995

[79] MühlenhoffU, MolikS, GodoyJ R, UzarskaM A, RichterN, SeubertA, ZhangY, StubbeJ, PierrelF, HerreroE, LilligC H, LillR (2010). Cytosolic monothiol glutaredoxins function in intracellular iron sensing and trafficking via their bound iron-sulfur cluster. Cell Metab, 12(4): 373–385

[80] NakanoK, BálintE, AshcroftM, VousdenK H (2000). A ribonucleotide reductase gene is a transcriptional target of p53 and p73. Oncogene, 19(37): 4283–4289

[81] NetzD J, StümpfigM, DoréC, MühlenhoffU, PierikA J, LillR (2010). Tah18 transfers electrons to Dre2 in cytosolic iron-sulfur protein biogenesis. Nat Chem Biol, 6(10): 758–765

[82] NiidaH, KatsunoY, SengokuM, ShimadaM, YukawaM, IkuraM, IkuraT, KohnoK, ShimaH, SuzukiH, TashiroS, NakanishiM (2010). Essential role of Tip60-dependent recruitment of ribonucleotide reductase at DNA damage sites in DNA repair during G1 phase. Genes Dev, 24(4): 333–338

[83] NordlundP, ReichardP (2006). Ribonucleotide reductases. Annu Rev Biochem, 75(1): 681–706

[84] NyholmS, ThelanderL, GräslundA (1993). Reduction and loss of the iron center in the reaction of the small subunit of mouse ribonucleotide reductase with hydroxyurea. Biochemistry, 32(43): 11569–11574

[85] OffenbacherA R, VassilievI R, SeyedsayamdostM R, StubbeJ, BarryB A (2009). Redox-linked structural changes in ribonucleotide reductase. J Am Chem Soc, 131(22): 7496–7497

[86] OrmöM, deMaréF, RegnströmK, AbergA, SahlinM, LingJ, LoehrT M, Sanders-LoehrJ, SjöbergB M (1992). Engineering of the iron site in ribonucleotide reductase to a self-hydroxylating monooxygenase. J Biol Chem, 267(13): 8711–8714

[87] OrtigosaA D, HristovaD, PerlsteinD L, ZhangZ, HuangM, StubbeJ (2006). Determination of the in vivo stoichiometry of tyrosyl radical per betabeta’ in Saccharomyces cerevisiae ribonucleotide reductase. Biochemistry, 45(40): 12282–12294

[88] PollycoveM, MaqsoodM (1962). Existence of an erythropoietic labile iron pool in animals. Nature, 194(4824): 152–154

[89] Pujol-CarrionN, BelliG, HerreroE, NoguesA, de la Torre-RuizM A (2006). Glutaredoxins Grx3 and Grx4 regulate nuclear localisation of Aft1 and the oxidative stress response in Saccharomyces cerevisiae. J Cell Sci, 119(Pt 21): 4554–4564

[90] ReeceS Y, HodgkissJ M, StubbeJ, NoceraD G (2006). Proton-coupled electron transfer: the mechanistic underpinning for radical transport and catalysis in biology. Philos Trans R Soc Lond B Biol Sci, 361(1472): 1351–1364

[91] ReichardP (1988). Interactions between deoxyribonucleotide and DNA synthesis. Annu Rev Biochem, 57(1): 349–374

[92] ReichardP (1993). From RNA to DNA, why so many ribonucleotide reductases? Science, 260(5115): 1773–1777

[93] RenS, WangR, KomatsuK, Bonaz-KrauseP, ZyrianovY, McKennaC E, CsipkeC, TokesZ A, LienE J (2002). Synthesis, biological evaluation, and quantitative structure-activity relationship analysis of new Schiff bases of hydroxysemicarbazide as potential antitumor agents. J Med Chem, 45(2): 410–419

[94] RichardsonD R, KalinowskiD S, RichardsonV, SharpeP C, LovejoyD B, IslamM, BernhardtP V (2009). 2-Acetylpyridine thiosemicarbazones are potent iron chelators and antiproliferative agents: redox activity, iron complexation and characterization of their antitumor activity. J Med Chem, 52(5): 1459–1470

[95] RofougaranR, VodnalaM, HoferA (2006). Enzymatically active mammalian ribonucleotide reductase exists primarily as an alpha6beta2 octamer. J Biol Chem, 281(38): 27705–27711

[96] RouaultT, KlausnerR (1997). Regulation of iron metabolism in eukaryotes. Curr Top Cell Regul, 35: 1–19

[97] SaitoY, ShibayamaH, TanakaH, TanimuraA, MatsumuraI, KanakuraY (2011). PICOT is a molecule which binds to anamorsin. Biochem Biophys Res Commun, 408(2): 329–333

[98] SaldivarJ C, MiumaS, BeneJ, HosseiniS A, ShibataH, SunJ, WheelerL J, MathewsC K, HuebnerK (2012). Initiation of genome instability and preneoplastic processes through loss of Fhit expression. PLoS Genet, 8(11): e1003077

[99] SaloweS, BollingerJ M Jr, AtorM, StubbeJ, McCrakenJ, PeisachJ, SamanoM C, RobinsM J (1993). Alternative model for mechanism-based inhibition of Escherichia coli ribonucleotide reductase by 2′-azido-2′-deoxyuridine 5′-diphosphate. Biochemistry, 32(47): 12749–12760

[100] SanvisensN, de LlanosR, PuigS (2013). Function and regulation of yeast ribonucleotide reductase: cell cycle, genotoxic stress, and iron bioavailability. Biomed J, 36: 51–58

[101] ScozzafavaA, SupuranC T (2003). Hydroxyurea is a carbonic anhydrase inhibitor. Bioorg Med Chem, 11(10): 2241–2246

[102] ShaoJ, LiuX, ZhuL, YenY (2013). Targeting ribonucleotide reductase for cancer therapy. Expert Opin Ther Targets, 17(12): 1423–1437

[103] ShaoJ, ZhouB, Di BilioA J, ZhuL, WangT, QiC, ShihJ, YenY (2006). A Ferrous-Triapine complex mediates formation of reactive oxygen species that inactivate human ribonucleotide reductase. Mol Cancer Ther, 5(3): 586–592

[104] ShaoJ, ZhouB, ZhuL, QiuW, YuanY C, XiB, YenY (2004). In vitro characterization of enzymatic properties and inhibition of the p53R2 subunit of human ribonucleotide reductase. Cancer Res, 64(1): 1–6

[105] ShibayamaH, TakaiE, MatsumuraI, KounoM, MoriiE, KitamuraY, TakedaJ, KanakuraY (2004). Identification of a cytokine-induced antiapoptotic molecule anamorsin essential for definitive hematopoiesis. J Exp Med, 199(4): 581–592

[106] SjöbergB M, ReichardP (1977). Nature of the free radical in ribonucleotide reductase from Escherichia coli. J Biol Chem, 252(2): 536–541

[107] SongS, PursellZ F, CopelandW C, LongleyM J, KunkelT A, MathewsC K (2005). DNA precursor asymmetries in mammalian tissue mitochondria and possible contribution to mutagenesis through reduced replication fidelity. Proc Natl Acad Sci USA, 102(14): 4990–4995

[108] SouglakosJ, BoukovinasI, TaronM, MendezP, MavroudisD, TripakiM, HatzidakiD, KoutsopoulosA, StathopoulosE, GeorgouliasV, RosellR (2008). Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel/gemcitabine. Br J Cancer, 98(10): 1710–1715

[109] StubbeJ (2003). Di-iron-tyrosyl radical ribonucleotide reductases. Curr Opin Chem Biol, 7(2): 183–188

[110] StubbeJ, CotruvoJ A Jr (2011). Control of metallation and active cofactor assembly in the class Ia and Ib ribonucleotide reductases: diiron or dimanganese? Curr Opin Chem Biol, 15(2): 284–290

[111] StubbeJ, GeJ, YeeC S (2001). The evolution of ribonucleotide reduction revisited. Trends Biochem Sci, 26(2): 93–99

[112] StubbeJ, van Der DonkW A (1998). Protein Radicals in Enzyme Catalysis. Chem Rev, 98(2): 705–762

[113] TanakaH, ArakawaH, YamaguchiT, ShiraishiK, FukudaS, MatsuiK, TakeiY, NakamuraY (2000). A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature, 404(6773): 42–49

[114] ThelanderL, GräslundA, ThelanderM (1983). Continual presence of oxygen and iron required for mammalian ribonucleotide reduction: possible regulation mechanism. Biochem Biophys Res Commun, 110(3): 859–865

[115] WangJ, LohmanG J, StubbeJ (2007). Enhanced subunit interactions with gemcitabine-5′-diphosphate inhibit ribonucleotide reductases. Proc Natl Acad Sci USA, 104(36): 14324–14329

[116] WhiteM F, DillinghamM S (2012). Iron-sulphur clusters in nucleic acid processing enzymes. Curr Opin Struct Biol, 22(1): 94–100

[117] WillingA, FollmannH, AulingG (1988). Ribonucleotide reductase of Brevibacterium ammoniagenes is a manganese enzyme. Eur J Bio, 170: 603–611

[118] WuC H, JiangW, KrebsC, StubbeJ (2007). YfaE, a ferredoxin involved in diferric-tyrosyl radical maintenance in Escherichia coli ribonucleotide reductase. Biochemistry, 46(41): 11577–11588

[119] WuX, HuangM (2008). Dif1 controls subcellular localization of ribonucleotide reductase by mediating nuclear import of the R2 subunit. Mol Cell Biol, 28(23): 7156–7167

[120] XueL, ZhouB, LiuX, QiuW, JinZ, YenY (2003). Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits. Cancer Res, 63(5): 980–986

[121] YangF D, SpanevelloR A, CelikerI, HirschmannR, RubinH, CoopermanB S (1990). The carboxyl terminus heptapeptide of the R2 subunit of mammalian ribonucleotide reductase inhibits enzyme activity and can be used to purify the R1 subunit. FEBS Lett, 272(1-2): 61–64

[122] YaoR, ZhangZ, AnX, BucciB, PerlsteinD L, StubbeJ, HuangM (2003). Subcellular localization of yeast ribonucleotide reductase regulated by the DNA replication and damage checkpoint pathways. Proc Natl Acad Sci USA, 100(11): 6628–6633

[123] YeH, RouaultT A (2010). Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease. Biochemistry, 49(24): 4945–4956

[124] YenY, GrillS P, DutschmanG E, ChangC N, ZhouB S, ChengY C (1994). Characterization of a hydroxyurea-resistant human KB cell line with supersensitivity to 6-thioguanine. Cancer Res, 54(14): 3686–3691

[125] YuY, WongJ, LovejoyD B, KalinowskiD S, RichardsonD R (2006). Chelators at the cancer coalface: desferrioxamine to Triapine and beyond. Clin Cancer Res, 12(23): 6876–6883

[126] ZeidnerJ F, KarpJ E, BlackfordA L, SmithB D, GojoI, GoreS D, LevisM J, CarrawayH E, GreerJ M, IvyS P, PratzK W, McDevittM A (2013). Phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms. Haematologica,

[127] ZhangY, LiuL, WuX, AnX, StubbeJ, HuangM (2011). Investigation of in vivo diferric tyrosyl radical formation in Saccharomyces cerevisiae Rnr2 protein: requirement of Rnr4 and contribution of Grx3/4 AND Dre2 proteins. J Biol Chem, 286(48): 41499–41509

[128] ZhangY, LyverE R, Nakamaru-OgisoE, YoonH, AmuthaB, LeeD W, BiE, OhnishiT, DaldalF, PainD, DancisA (2008). Dre2, a conserved eukaryotic Fe/S cluster protein, functions in cytosolic Fe/S protein biogenesis. Mol Cell Biol, 28(18): 5569–5582

[129] ZhaoX, ChabesA, DomkinV, ThelanderL, RothsteinR (2001). The ribonucleotide reductase inhibitor Sml1 is a new target of the Mec1/Rad53 kinase cascade during growth and in response to DNA damage. EMBO J, 20(13): 3544–3553

[130] ZuckermanJ E, HsuehT, KoyaR C, DavisM E, RibasA (2011). siRNA knockdown of ribonucleotide reductase inhibits melanoma cell line proliferation alone or synergistically with temozolomide. J Invest Dermatol, 131(2): 453–460

Acknowledgements

This work was supported by National Institutes of Health (CA125574 and GM81393).

Compliance with ethics guidelines

The authors declare no conflict of interest.

This article does not contain any studies with human or animal as subjects performed by any of the authors.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg