5.4 Methoden
5.4.2 Proteinbiochemische Methoden
5.4.3.3 Aminolyse der Esterbindung
Nach der Automodifikation von ARTD1 unter Verwendung des NAD+ Analogons 5 und der Click-Reaktion mit Biotin-Azid wurden die Streptavidin-haltigen Ma-gnetk¨ugelchen ins Reaktionsgemisch gegeben und f¨ur eine weitere Stunde bei 25 ◦C inkubiert. Anschließend wurde die oben stehende L¨osung durch 2 Min Zentrifuga-tion bei 12000 × g von den Magnetk¨ugelchen abgetrennt. Die proteingebundenen Streptavidin-haltigen Magnetk¨ugelchen wurden dreimal mit PBS gewaschen.
Methode 1:
Nach dem letzten Waschschritt wurden die Magnetk¨ugelchen in tridestilliertem Was-ser suspendiert. Ein Amin (Methylamin, Ethanolamin und Hydrazin) wurde in die Suspension zugegeben, so dass sie eine Konzentration des Amins von 10 % (v/v) ent-hielt. Die Mischung wurde danach 30 Min bei 25◦C inkubiert. Nach der Abtrennung der Magnetk¨ugelchen durch 2 Min Zentrifugation 12000×g wurden die Proben unter vermindertem Druck konzentriert, durch den SDS-PAGE Ladepuffer denaturiert und dann mittels der SDS-PAGE Gelelektrophorese analysiert.
Methode 2:
Nach dem letzten Waschschritt wurden die Magnetk¨ugelchen im 100 mM HEPES-Puffer suspendiert. Das Hydroxylamin wurde dann in die Mischung zugegeben, so dass sie eine Endkonzentration des Amins von 100 mM enthielt. Die Mischung wur-de 1 Stunwur-de bei 50 ◦C erw¨armt. Nach der Abtrennung der Magnetk¨ugelchen durch 2 Min Zentrifugation bei 12000 × g wurden die Proben unter vermindertem Druck konzentriert, durch den PAGE Ladepuffer denaturiert und dann mittels der SDS-PAGE Gelelektrophorese analysiert.
Methode 3:
Nach der Automodifikation von ARTD1 unter Verwendung des NAD+ Analogons 5 wurden die Proben mit Sulfo-Cy5-Azid geclickt. Der ¨Uberschuss von Sulfo-Cy5-Azid wurde durch eine SephadexT M G-25 Minis¨aule f¨ur 3 Min bei 12000 ×g entfernt. An-schließend wurden die Proben mit dem Hydroxylamin (100 mM Endkonzentration) gemischt und 1 Stunde bei 50◦C erw¨armt, danach durch den SDS-PAGE Ladepuffer denaturiert und dann mittels der SDS-PAGE Gelelektrophorese analysiert.
5.4.3.4 Pulldown-Experiment von Histon H1.2
F¨ur die Trans(ADP-Ribos)ylierung von Histon H1.2 wurden 150nM human ARTD1, 113 µM Histon H1,2, 13,5 µM EcoRI und 2 mM nat¨urliches bzw. NAD+ Ana-loga 1 und 5 im Reaktionspuffer zusammen gemischt. Die Reaktionen wurden im Thermocycler 20 Min bei 37 ◦C inkubiert. Durch Abk¨uhlung auf 4 ◦C wurden die Reaktionen beendet. Danach wurden die erhaltenen Produkte direkt in die Click-Reaktion (8mM CuSO4, 4mM Biotin-Azid, 40mM BTTAA und 64mM Natrium-L-Ascorbat) und anschließend mit den Streptavidin-haltige Magnetk¨ugelchen in den Affinit¨atsaufreinigungsschritt[182] eingesetzt. Nach dem letzten Waschschritt wurden die proteingebundenen Streptavidin-haltigen Magnetk¨ugelchen in 20 mM Tris-HCl (pH 7,4) suspendiert. Die Proben wurden mit 6 × SDS-PAGE Ladepuffer versetzt und 15 Min bei 95 ◦C erhitzt. Anschließend wurde die oben stehende L¨osung durch 2 Min Zentrifugation bei 12000 × g von den Magnetk¨ugelchen abgetrennt und die Proben wurden dann mittels der SDS-PAGE Gelelektrophorese analysiert.
Kapitel 6
Abk¨ urzungsverzeichnis
3-AB 3-Aminobenzamid
Ac Acetyl
ACN Acetonitril
ADPR ADP-Ribose
ADPRC ADP-Ribosyl-Cyclasen
abs. absolut
ART ADP-Ribosyltransferase
ARTD ADP-Ribosyltransferase Diphtherietoxin-¨ahnlich
ARTs ADP-Ribosyltransferasen
AMP Adenosinmonophosphat
AP Apurine/Apyrimidine
APE Apurinische/apyrimidinische Endonuklease
APS Ammoniumperoxodisulfat
Asp Asparagins¨aure (D)
ATM Ataxia telangiectasia mutated
BCIP 5-Brom-4-chlor-3-indolylphosphat
BER Basenexzisionsreparatur
BOP Benzotriazolyloxytris(dimethylamino)phosphonium Hexafluorophosphat
br Breiter
BRCA1 Breast cancer 1, early onset BRCA2 Breast cancer 2, early onset
BRCT Breast Cancer Carboxaterminal
D2O Deuteriumoxid (Schweres Wasser)
d Duplett
ddd Duplett vom Duplett vom Duplett
ddH2O Tridestilliertes Wasser
ddt Duplett vom Duplett vom Triplett
DEVD Einbuchstabencode der Aminos¨auren: Asp-Glu-Val-Asp
d.h. Das heißt
DIFO Difluoriertes Cyclooctin
DMAP 4-(Dimethylamino)pyridin
DMF Dimethylformamid
DNA Desoxyribonukleins¨aure
DNA-PKCS DNA-abh¨angige Proteinkinase katalytische Untereinheit
dq Duplett vom Quartett
Ku80 XRCC5
MRN Ein Proteinkomplex aus Mre11, Rad50 und Nbs1
Q Einbuchstabencode des Glutamins
XLF XRCC4-¨ahnlicher Faktor
XRCC1 X-ray repair cross-complementing protein 1 XRCC4 X-ray repair cross-complementing protein 4
Kapitel 7
Literaturverzeichnis
Literaturverzeichnis
[1] A. Harden, W. J. Young: The alcoholic ferment of yeast-juice. Part II.–The Conferment of Yeast-Juice, Proc. R. Soc. B,1906,78, 369-375.
[2] H. von Euler, R. Vestin: Zur Kenntnis der Wirkungen der Co-Zymase, Z. phy-siol. Chem., 1935, 237, 1-5; H. von Euler, H. Albers, F. Schlenk: Chemische Untersuchungen an hochgereinigter Co-Zymase, Z. Physiol. Chem.,1936,240, 113-126.
[3] O. Warburg, W. Christian, A. Griese: Wasserstoff¨ubertragendes Co-Ferment, seine Zusammensetzung und Wirkungsweise, Biochem. Z., 1935,282, 157-205;
O. Warburg, W. Christian: Pyridin, der wasserstoff¨ubertragene Bestandteil von G¨arungsfermenten, Biochem. Z., 1936, 287, 291-328.
[4] T. Honjo, Y. Nishizuka, O. Hayaishi, I. Kato: Diphtheria toxin-dependent ade-nosine diphosphate ribosylation of aminoacyl transferase II and inhibition of protein synthesis, J. Biol. Chem., 1968, 243, 3553-3555.
[5] M. O. Hottiger, P. O. Hassa, B. L¨uscher, H. Sch¨uler, F. Koch-Nolte: Toward a unified nomenclature for mammalian ADP-ribosyltransferases,Trends Biochem Sci., 2010, 35, 208-219.
[6] A. A. Sauve, C. Wolberger, V. L. Schramm, J. D. Boeke: The biochemistry of sirtuins, Annu. Rev. Biochem.,2006,75, 435-465.
[7] R. Ramakrishna, J. S. Edwards, A. McCulloch, B. O. Palsson: Flux-balance analysis of mitochondrial energy metabolism: consequences of systemic
stoi-chiometric constraints, Am. J Physiol. Regul. Integr. Comp. Physiol., 2001, 280, R695-R704.
[8] H. R. Horton, L. A. Moran, K. G. Scrimgeour, M. D. Perry, J. D. Rawn, Bioche-mie, Addison-Wesley Verlag; Auflage: 4., aktualisierte Auflage (29. Juli 2008), ISBN: 978-3-8273-7321-0.
[9] F. Berger, M. H. Ram´ırez-Hern´andez, M. Ziegler: The new life of a centenarian:
signalling functions of NAD(P), Trends in Biochem. Sci., 2004, 29, 111-118.
[10] C. Cant´o, A. A. Sauve, P. Bai: Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes, Mol. Asp. Med., 2013, 34, 1168-1201.
[11] K. G. Tanne, J. Landry, R. Sternglanz, J. M. Denu: Silent information regulator 2 family of NAD-dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose,Proc. Natl. Acad. Sci. USA,2000, 97, 14178-14182; J. C. Tanny, D. Moazed: Coupling of histone deacetylation to NAD breakdown by the yeast silencing protein Sir2: Evidence for acetyl transfer from substrate to an NAD breakdown product, Proc. Natl. Acad. Sci. USA, 2001, 98, 415-420.
[12] S. Imai, C. M. Armstrong, M. Kaeberlein, L. Guarente: Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase, Nature, 2000, 403, 795-800.
[13] L. Tong, J. M. Denu: Function and metabolism of sirtuin metabolite O-acetyl-ADP-ribose, BBA-Proteins and Proteom.,2010,1804, 1617-1625.
[14] D. L. Clapper, T. F. Walseth, P. J. Dargie, H. C. Lee: Pyridine nucleotide metabolites stimulate calcium release from sea urchin microsomes desensitized to inositol trisphosphate, J. Biol. Chem., 1987, 262, 9561-9568.
[15] H. C. Lee, R. Aarhus, D. Levitt: The crystal structure of cyclic ADP-ribose, Nat. Struct. Mol. Biol., 1994, 1, 143-144.
[16] D. J. States, T. F. Walseth, H. C. Lee: Similarities in amino acid sequences of aplysia ADP-ribosyl cyclase and human lymphocyte antigen CD38, Trends in Biochem. Sci., 1992, 17, 495-497.
[17] M. R. Hellmich, F. Strumwasser: Purification and characterization of a mol-luscan egg-specific NADase, a second-messenger enzyme, Cell. Regul., 1991, 2, 193-202; D. L. Glick, M. R. Hellmich, S. Beushausen, P. Tempst, H. Bay-ley, F. Strumwasser: Primary structure of a molluscan egg-specific NADase, asecond-messenger enzyme, Cell. Regul., 1991, 2, 211-217.
[18] S. Yamamoto-Katayama, A. Sato, M. Ariyoshi, M. Suyama, K. Ishihara, T.
Hirano, H. Nakamura, K. Morikawa, H. Jingami: Site-directed removal of N-glycosylation sites in BST-1/CD157: effects on molecular and functional hete-rogeneity, Biochem. J., 2001, 357, 385-392.
[19] A. H. Guse: Biochemistry, biology, and pharmacology of cyclic adenosine di-phosphoribose (cADPR), Curr. Med. Chem., 2004, 11, 847-855.
[20] A. H. Guse: Regulation of calcium signaling by the second messenger cyclic adenosine diphosphoribose (cADPR), Curr. Med. Chem., 2004, 4, 239-246.
[21] P. Belenky, K. L. Bogan, C. Brenner: NAD+ metabolism in health and disease, Trends in Biochem. Sci.,2007,32, 12-19.
[22] A. Mattevi: A close look at NAD biosynthesis, Nat. Struct. Mol. Biol., 2006, 13, 563-564.
[23] V. Sharma, C. Grubmeyer, J. C. Sacchettini: Crystal structure of quinolinic acid phosphoribosyltransferase from mycobacterium tuberculosis: A potential TB drug target, Structure, 1998, 6, 1587-1599; D. H. Shin, N. Oganesyan, J.
Jancarik, H. Yokota, R. Kim, S.-H. Kim: Crystal structure of a nicotinate phos-phoribosyltransferase from thermoplasma acidophilum, J. Biol. Chem., 2005, 280, 18326-18335; J. S. Chappie, J. M. C`anaves, G. W. Han, C. L. Rife, Q. P.
Xu, R. C. Stevens: The structure of a eukaryotic nicotinic acid phosphoribosyl-transferase reveals structural heterogeneity among type II PRTases, Structure, 2005, 13, 1385-1396.
[24] V. Saridakis, D. Christendat, M. S. Kimber, A. Dharamsi, A. M. Edwards, E.
F. Pai: Insights into ligand binding and catalysis of a central step in NAD+ synthesis: structures of methanobacterium thermoautotrophicum NMN adeny-lyltransferase complexes, J. Biol. Chem., 2001, 276, 7225-7232; S. Garavag-lia, I. D’Angelo, M. Emanuelli, F. Carnevali, F. Pierella, G. Magni, M. Rizzi:
Structure of human NMN adenylyltransferase: A key nuclear enzyme for NAD homeostasis, J. Biol. Chem., 2002, 277, 8524-8530; T. J. Zhou, O. Kurnasov, D. R. Tomchick, D. D. Binns, N. V Grishin, V. E. Marquez, A. L. Osterman, H. Zhang: Structure of human nicotinamide/nicotinic acid mononucleotide ade-nylyltransferase: Basis for the dual substrate specificity and activation of the oncolytic agent tiazofurin, J. Biol. Chem., 2002, 277, 13148-13154; H. Zhang, T. J. Zhou, O. Kurnasov, S. Cheek, N. V Grishin, A. Osterman: Crystal struc-tures of E. coli nicotinate mononucleotide adenylyltransferase and its complex with deamido-NAD, Structure, 2002, 10, 69-79.
[25] E. M. Sletten, C. R. Bertozzi: Bioorthogonale Chemie - oder: in einem Meer aus Funktionalit¨at nach Selektivit¨at fischen,Angew. Chem.,2009,121, 7108-7133.
[26] E. M. Sletten, C. R. Bertozzi: From mechanism to mouse: A tale of two bioor-thogonal reactions, Acc. Chem. Res., 2011, 44, 666-676.
[27] G. U. Nienhaus: Das gr¨un fluoreszierende Protein: Schl¨ussel zur Untersuchung chemischer Prozesse in lebenden Zellen, Angew. Chem., 2008, 120, 9130-9132.
[28] J. M. Baskin C. R. Bertozzi: Bioorthogonal click chemistry: Covalent labeling in living systems,QSAR Comb. Sci.,2007,26, 1211-1219; C. P. R. Hackenber-ger, D. Schwarzer: Chemoselektive Ligations- und Modifikationsstrategien f¨ur Peptide und Proteine, Angew. Chem., 2008, 120, 10182-10228.
[29] S. Br¨ase, C. Gil, K. Knepper, V. Zimmerman: Organische Azide - explodierende Vielfalt bei einer einzigartigen Substanzklasse,Angew. Chem.,2005,117, 5320-5374; M. F. Debets, C. W. J. van der Doelen, F. P. J. T. Rutjes, F. L. van Delft:
Azide: A unique dipole for metal-free bioorthogonal ligations, ChemBioChem, 2010,11, 1168-1184.
[30] R. J. Griffin: The medicinal chemistry of the azido group, Prog. Med. Chem., 1994,31, 121-232.
[31] A. Michael: Ueber die Einwirkung von Diazobenzolimid auf Acetylendicarb-ons¨auremethylester, J. Prakt. Chem.,1893, 48, 94-95.
[32] R. Huisgen: 1.3-Dipolare Cycloadditionen R¨uckschau und Ausblick, Angew.
Chem.,1963, 75, 604-637.
[33] H. C. Kolb, M. G. Finn, K. B. Sharpless: Click-Chemie: Diverse chemische Funktionalit¨at mit einer Handvoll guter Reaktionen,Angew. Chem.,2001,113, 2056-2075.
[34] F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B. Sharp-less, V. V. Fokin: Copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates, J. Am. Chem. Soc., 2005, 127, 210-216.
[35] V. D. Bock, H. Hiemstra, J. H. van Maarseveen: Cu(I)-catalyzed alkyne-azide
“click” cycloadditions from a mechanistic and synthetic perspective, Eur. J.
Org. Chem., 2006, 1, 51-68.
[36] K. B. Sharpless, E. van der Eycken: Click chemistry (siehe gesamtes Heft), QSAR Comb. Sci., 2007, 26, 1110-1323.
[37] F. Wolbers, P. ter Braak, S. Le Gac, R. Luttge, H. Andersson, I. Vermes, A.
van den Berg: Viability study of HL60 cells in contact with commonly used microchip materials, Electrophoresis,2006,27, 5073-5080.
[38] G. Wittig, A. Krebs: Zur Existenz niedergliedriger Cycloalkine, Chem. Ber., 1961, 94, 3260-3275.
[39] E. M. Sletten, C. R. Bertozzi: A hydrophilic azacyclooctyne for Cu-free click chemistry,Org. Lett., 2008, 10, 3097-3099.
[40] X. H. Ning, J. Guo, M. A. Wolfert, G. J. Boons: Visualizing metabolically labeled glycoconjugates of living cells by copper-free and fast Huisgen cycload-ditions,Angew. Chem.,2008,120, 2285-2287.
[41] J. M. Baskin, J. A. Prescher, S. T. Laughlin, N. J. Agard, P. V. Chang, I. A.
Miller, A. Lo, J. A. Codelli, C. R. Bertozzi: Copper-free click chemistry for dynamicin vivo imaging, Proc. Natl. Acad. Sci. USA,2007,104, 16793-16797;
S. T. Laughlin, J. M. Baskin, S. L. Amacher, C. R. Bertozzi: In vivo imaging of membrane-associated glycans in developing zebrafish, Science, 2008, 320, 664-667.
[42] E. Saxon, C. R. Bertozzi: Cell surface engineering by a modified Staudinger reaction, Science,2000,287, 2007-2010.
[43] H. Staudinger, J. Meyer: ¨Uber neue organische Phosphorverbindungen III.
Phosphinmethylenderivate und Phosphinimine,Helv. Chim. Acta,1919,2, 635-646.
[44] D. H. Dube C. R. Bertozzi: Glycans in cancer and inflammation - potential for therapeutics and diagnostics, Nat. Rev. Drug. Discov., 2005, 4, 477-488.
[45] S. S. van Berkel, M. B. van Eldijk, J. C. M. van Hest: Staudinger-Ligation als Methode zur Biokonjugation,Angew. Chem.,2011,123, 8968-8989.
[46] B. L. Nilsson, L. L. Kiessling, R. T. Raines: Staudinger ligation a peptide from a thioester and azide, Org. Lett., 2000, 2, 1939-1941
[47] E. Saxon, J. I. Armstrong, C. R. Bertozzi: A “traceless” Staudinger ligation for the chemoselective synthesis of amide bonds, Org. Lett., 2000, 2, 2141-2143.
[48] P. E. Dawson, T. W. Muir, I. Clark-Lewis, S. B. Kent: Synthesis of proteins by native chemical ligation, Science,1994,266, 776-779.
[49] M. L. Blackman, M. Royzen, J. M. Fox: Tetrazine ligation: Fast bioconjugation based on inverse-electron-demand diels-alder reactivity, J. Am. Chem. Soc., 2008,130, 13518-13519.
[50] A. H. Guse, X. F. Gu, L. R. Zhang, K. Weber, E. Kr¨amer, Z. J. Yang, H. W.
Jin, Q. Li, L. Carrier, L. H. Zhang: A minimal structural analogue of cyclic ADP-ribose: synthesis and calcium release activity in mammalian cells,J. Biol.
Chem.,2005, 280, 15952-15959.
[51] S. Bruzzone, A. D. Flora, C. Usai, R. Graeff, H. C. Lee: Cyclic ADP-ribose is a second messenger in the lipopolysaccharide-stimulated proliferation of human peripheral blood mononuclear cells, Biochem. J., 2003, 375, 395-403.
[52] M. A. Blasco: Telomeres and human disease: ageing, cancer and beyond, Nat.
Rev. Genet., 2005, 6, 611-622.
[53] M. C. Gendron, N. Schrantz, D. M´etivier, G. Kroemer, Z. Maciorowska, F.
Sureau, S. Koester, P. X. Petit: Oxidation of pyridine nucleotides during fas-and ceramide-induced apoptosis in Jurkat cells: Correlation with changes in mitochondria, glutathione depletion, intracellular acidification and caspase 3 activation, Biochem. J., 2001, 353, 357-367.
[54] S. Mandir, C. M. Simbulan-Rosenthal, M. F. Poitras, J. P. Lumpkin, V. L.
Dawson, M. E. Smulson, T. M. Dawson: A novel in vivo post-translational mo-dification of p53 by PARP-1 in MPTP-induced parkinsonism, J. Neurochem., 2002,83, 186-192.
[55] M. D. Girolamo, N. Dani, A. Stilla, D. Corda: Physiological relevance of the endogenous mono(ADP-ribosyl)ation of cellular proteins, FEBS J.,2005,272,
4565-4575; S. Michan, D. Sinclair: Sirtuins in mammals: insights into their biological function, Biochem. J., 2007, 404, 1-13.
[56] M. Seman, S. Adriouch, F. Scheuplein, C. Krebs, D. Freese, G. Glowacki, P.
Deterre, F. Haag, F. Koch-Nolte: NAD-induced T cell death,Immunity,2003, 19, 571-582; E. K. Song, Y. R. Lee, H. N. Yu, U. H. Kim, S. Y. Rah, K. H.
Park, I. K. Shim, S. J. Lee, Y. M. Park, W. G. Chung, J. S. Kim, M. K: Han:
Extracellular NAD is a regulator for FcγR-mediated phagocytosis in murine macrophages,Biochem. Biophys. Res. Com., 2008, 367, 156-161.
[57] J. A. Birrell, J. Hirst: Investigation of NADH binding, hydride transfer, and NAD+ dissociation during NADH oxidation by mitochondrial complex I using modified nicotinamide nucleotides, Biochemistry, 2013, 52, 4048-4055.
[58] Y. Hatefi, A. G. Haavik, D. E. Griffiths: Studies on the electron transfer system.
Preparation and properties of mitochondrial DPNH-coenzyme Q reductase. J.
Biol. Chem., 1962, 237, 1676-1680.
[59] U. Brandt, S. Kerscher, S. Drose, K. Zwicker, V. Zickermann: Proton pumping by NADH: ubiquinone oxidoreductase. A redox driven conformational change mechanism? FEBS Lett.,2003,545, 9-17.
[60] W. Q. Liu, A. A. Gahr, R. Bao, Y. Z. Li: Recent progress in the synthesis and evaluation of azido and diazo derivatives of NAD+ for photoaffinity labeling experiments, Trends in Org. Chem.,1997,6, 219-230.
[61] H. Bayley: Laboratory techniques in biochemistry and molecular biology,1983, Vol. 12, Elsevier Verlag, ISBN: 978-0-444-80530-0.
[62] H. Jiang, J. Congleton, Q. Liu, P. Merchant, F. Malavasi, H. C. Lee, Q. Hao, A. Yen, H. Lin: Mechanism-based small molecule probes for labeling CD38 on live cells, J. Am. Chem. Soc.,2009,131, 1658-1659.
[63] J. T. Du, H. Jiang. H. Lin: Investigating the ADP-ribosyltransferase activity of sirtuins with NAD analogues and32P-NAD,Biochemistry,2009,48, 2878-2890.
[64] H. Jiang, J. H. Kim, K. M. Frizzell, W. L. Kraus, H. Lin: Clickable NAD analogues for labeling substrate proteins of poly(ADP-ribose) polymerases, J.
Am. Chem. Soc., 2010, 132, 9363-9372.
[65] L. M. Coetzee, S. S. Tay, D. Lawrie, G. Janossy, D. K. Glencross: From research tool to routine test: CD38 monitoring in HIV patients, Cyto. Part B: Clin.
Cytom., 2009, 76B, 375-384.
[66] K. A. Wall, M. Klis, J. Kornet, D. Coyle, J.-C. Am´e, M. K. Jacobson, J. T.
Slama: Inhibition of the intrinsic NAD+ glycohydrolase activity of CD38 by carbocyclic NAD analogues, Biochem. J.,1998,335, 631-636.
[67] P. Franchetti, L. Cappellacci, P. Perlini, H. N. Jayaram, A. Butler, B. P. Schnei-der, F. R. Collart, E. Huberman, M. Grifantini: Isosteric analogues of nicotina-mide adenine dinucleotide derived from furanfurin, thiophenfurin, and seleno-phenfurin as mammalian inosine monophosphate dehydrogenase (type I and II) inhibitors, J. Med. Chem., 1998,41, 1702-1707; P. Franchetti, L. Cappellacci, S. Marchetti, C. Martini, B. Costa, K. Varani, P. A. Borea, M. Grifantini: C-nucleoside analogues of furanfurin as ligands to a1 adenosine receptors, Bioorg.
Med. Chem., 2000, 8, 2367-2373.
[68] K. W. Pankiewicz, K. A. Watanabe, K. Lesiak-Watanabe, B. M. Goldstein, H. N. Jayaram: The chemistry of nicotinamide adenine dinucleotide (NAD) analogues containing C-nucleosides related to nicotinamide riboside,Curr. Med.
Chem.,2002, 9, 733-741.
[69] N. E. Batoux, F. Paradisi, P. C. Engel, M. E. Migaud: Novel nicotinamide adeni-ne dinucleotide analogues as selective inhibitors of NAD+-dependent enzymes, Tetrahedron, 2004,60, 6609-6617.
[70] P. Chambon, J. D. Weill, P. Mandel: Nicotinamide mononucleotide activati-on of a new DNA-dependent polyadenylic acid synthesizing nuclear enzyme, Biochem. Biophys. Res. Com., 1963, 11, 39-43.
[71] D. D’Amours, S. Desnoyers, I. D’Silva, G. G. Poirier: Poly(ADP-ribosyl)ation reactions in the regulation of nuclear functions, Biochem. J., 1999, 342, 249-268.
[72] V. Schreiber, F. Dantzer, J. C. Ame, G. de Murcia: Poly(ADP-ribose): Novel functions for an old molecule, Nat. Rev. Mol. Cell Biol.,2006,7, 517-528.
[73] B. A. Gibson, W. L. Kraus: New insights into the molecular and cellular func-tions of poly(ADP-ribose) and PARPs, Nat. Rev. Mol. Cell Biol., 2012, 13, 411-424.
[74] J. Y´elamos, V. Schreiber, F. Dantzer: Toward specific functions of poly(ADP-ribose) polymerase-2, Trends in Mol. Med., 2008, 14, 169-178 (modifizierte Abbildung).
[75] T. Sugimura, S. Fujimura, S. Hasegawa, Y. Kawamura: Polymerization of the adenosine 5’-diphosphate ribose moiety of NAD by rat liver nuclear enzyme, Biochim. Biophys. Acta.,1967,138, 438-441.
[76] M. Ikejima, S. Noguchi, R. Yamashita, T. Ogura, T. Sugimura, D. M. Gill, M.
Miwa: The zinc fingers of human poly(ADP-ribose) polymerase are differenti-ally required for the recognition of DNA breaks and nicks and the consequent enzyme activation. Other structures recognize intact DNA, J. Biol. Chem., 1990, 265, 21907-21913.
[77] G. de Murcia, V. Schreiber, M. Molinete, B. Saulier, O. Poch, M. Masson, C. Niedergang, J. Menissier de Murcia: Structure and function of poly(ADP-ribose) polymerase, Mol. Cell. Biochem., 1994, 138, 15-24; S. Okano, L. Lan,
K. W. Caldecott, T. Mori, A. Yasui: Spatial and temporal cellular responses to single-strand breaks in human cells, Mol. Cell. Biol., 2003, 23, 3974-3981.
[78] M. Audebert, B. Salles, P. Calsou: Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining, J. Biol. Chem., 2004, 279, 55117-55126; E.
Kun, E. Kirsten, J. Mendeleyev, C. P. Ordahl: Regulation of the enzymatic catalysis of poly(ADP-ribose) polymerase by dsDNA, polyamines, Mg2+, Ca2+, histones H1 and H3, and ATP,Biochemistry,2004,43, 210-216; I. Lonskaya, V.
N. Potaman, L. S. Shlyakhtenko, E. A. Oussatcheva, Y. L. Lyubchenko, V. A.
Soldatenkov: Regulation of poly(ADP-ribose) polymerase-1 by DNA structure-specific binding, J. Biol. Chem., 2005, 280, 17076-17083.
[79] G. Gradwohl, J. M. M´enissier de Murcia, M. Molinete, F. Simonin, M. Koken, J. H. Hoeijmakers, G. de Murcia: The second zinc-finger domain of poly(ADP-ribose) polymerase determines specificity for single-stranded breaks in DNA, Proc. Natl. Acad. Sci. USA, 1990, 87, 2990-2994.
[80] S. F. El-Khamisy, M. Masutani, H. Suzuki, K. W. Caldecott: A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage, Nucleic Acids Res.,2003,31, 5526-5533.
[81] T. Kinoshita, I. Nakanishi, M. Warizaya, A. Iwashita, Y. Kido, K. Hattori, T.
Fujii: Inhibitor-induced structural change of the active site of human poly(ADP-ribose) polymerase, FEBS Lett., 2004, 556, 43-46.
[82] R. Martello, A. Mangerich, S. Sass, P. C. Dedon, A. B¨urkle: Quantification of cellular poly(ADP-ribosyl)ation by stable isotope dilution mass spectrometry reveals tissue- and drug-dependent stress response dynamics,ACS Chem. Biol., 2013,8, 1567-1575.
[83] M. Miwa, H. Saito, H. Sakura, N. Saikawa, F. Watanabe, T. Matsushima, T.
Sugimura: A13C NMR study of poly(adenosine diphosphate ribose) and its
mo-nomers: evidence of alpha-(100 leads to 20)ribofuranosyl ribofuranoside residue, Nucleic. Acids Res.,1977,4, 3997-4005.
[84] M. Miwa, N. Saikawa, Z. Yamaizumi, S. Nishimura, T. Sugimura: Structure of poly(adenosine diphosphate ribose): identification of 20-[100-ribosyl-200-(or 300 -)(1000-ribosyl)]adenosine-50,500,5000-tris(phosphate) as a branch linkage,Proc. Natl.
Acad. Sci. USA,1979, 76, 595-599.
[85] C. Cant´o, A. A. Sauve, P. Bai: Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes, Mol. Asp. Med., 2013, 34, 1168-1201.
[86] D. Slade, M. S. Dunstan, E. Barkauskaite, R. Weston, P. Lafite, N. Dixon, M.
Ahel, D. Leys, I. Ahel: The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase, Nature, 2011, 477, 616-620.
[87] J. Diefenbach, A. B¨urkle: Introduction to poly(ADP-ribose) metabolism, Cell.
Mol. Life Sci.,2005,62, 721-730.
[88] H. Lin: Nicotinamide adenine dinucleotide: beyond a redox coenzyme, Org.
Biomol. Chem., 2007, 5, 2541-2554.
[89] D. Cervantes-Laurean, D. E. Minte, E. L. Jacobson, M. K. Jacobson: Protein glycation by ADP-Ribose: Studies of model conjugatest, Biochemistry, 1993, 32, 1528-1534.
[90] Z. Tao, P. Gao, H. W. Liu: Identification of the ADP-ribosylation sites in the PARP-1 automodification domain: Analysis and implications, J. Am. Chem.
Soc., 2009, 131, 14258-14260.
[91] S. Messner, M. O. Hottiger: Histone ADP-ribosylation in DNA repair, replica-tion and transcripreplica-tion, Trends in Cell Biol., 2011,21, 534-542.
[92] H. Mendoza-Alvarez, R. Alvarez-Gonzalez: Regulation of p53 sequence-specific DNA-binding by covalent poly(ADP-ribosyl)ation, J. Biol. Chem.,2001, 276, 36425-36430.
[93] Y. Ohashi, K. Ueda, M. Kawaichi, O. Hayaishi: Activation of DNA ligase by poly(ADP-ribose) in chromatin, Proc. Natl. Acad. Sci. USA, 1983, 80, 3604-3607.
[94] H. Teraoka, K. Tsukada, A. Matsukage, T. Kamiya: Inhibition of DNA polyme-rase alpha, DNA polymepolyme-rase beta, terminal deoxynucleotidyl transfepolyme-rase, and DNA ligase II by poly(ADP-ribosyl)ation reaction in vitro,Biochem. Biophys.
Res. Com., 1985,128, 61-67.
[95] A. I. Scovassl, C. Mariani, M. Negroni, C. Negri, U. Bertazzoni: ADP-Ribosylation of nonhistone proteins in HeLa cells: Modification of DNA to-poisomerase II, Exp. Cell Res., 1993, 206, 177-181.
[96] T. Ruscetti, B. E. Lehnert, J. Halbrook, H. L. Trong, M. F. Hoekstra, D. J.
Chen, S. R. Peterson: Stimulation of the DNA-dependent protein kinase by poly(ADP-ribose) polymerase, J. Biol. Chem.,1998, 273, 14461-14467.
[97] R. Alvarez-Gonzalez, G. Pacheco-Rodriguez, H. Mendoza-Alvarez: Enzymology of ADP-ribose polymer synthesis, Mol. Cell Biochem., 1994, 138, 33-37.
[98] A. Ruf, J. M. de Murcia J, G. de Murcia, G. E. Schulz: Structure of the catalytic fragment of poly(ADribose) polymerase from chicken, Proc. Natl. Acad. Sci.
USA, 1996, 93, 7481-7485.
[99] D. Bellocchi, G. Costantino, R. Pellicciari, N. Re, A. Marrone, C. Coletti:
Poly(ADP-Ribose)-polymerase-catalyzed hydrolysis of NAD+: QM/MM simu-lation of the enzyme reaction, ChemMedChem, 2006, 1, 533-539.
[100] A. Ruf, V. Rolli, G.de Murcia, G. E. Schulz: The mechanism of the elongation and branching reaction of poly(ADP-ribose) polymerase as derived from crystal structures and mutagenesis, J. Mol. Biol., 1998, 278, 57-65.
[101] J. D Chapman, J.-P. Gagn´e, G. G. Poirier, D. R. Goodlett: Mapping PARP-1 auto-ADP-ribosylation sites by liquid chromatography-tandem mass spectro-metry, J. Proteome Res., 2013, 12, 1868-1880.
[102] Y. j. Zhang, J. q. Wang, M. Ding, Y. h. Yu: Site-specific characterization of the Asp- and Glu-ADP-ribosylated proteome, Nat. Methods, 2013, 10, 981-984.
[103] D. Cervantes-Laurean, D. E. Minte, E. L. Jacobson, M. K. Jacobson: Protein glycation by ADP-ribose: Studies of model conjugates,Biochemistry,1993,32, 1528-1534.
[104] C. J. Lord, A. Ashworth: The DNA damage response and cancer therapy, Na-ture,2012, 481, 287-294 (modifizierte Abbildung).
[105] K. W. Caldecott: Mammalian DNA single-strand break repair: an X-ra(y)ted affair,Bioessays,2001,23, 447-455; J. Fan J, D.M. Wilson III: Protein-protein interactions and posttranslational modifications in mammalian base excision repair, Free Radic. Biol. Med.,2005,38, 1121-1266.
[106] C. J. Park, B. S. Choi: The protein shuffle. Sequential interactions among com-ponents of the human nucleotide excision repair pathway,FEBS J.,2006, 273, 1600-1608.
[107] M. R. Lieber: The mechanism of human nonhomologous DNA end joining, J.
Biol. Chem., 2008, 283, 1-5.
[108] J. San Filippo, P. Sung, H. Klein: Mechanism of eukaryotic homologous recom-bination, Annu. Rev. Biochem., 2008, 77, 229-257.
[109] P. Hsieh, K. Yamane: DNA mismatch repair: Molecular mechanism, cancer, and ageing, Mech. Ageing Dev., 2008, 129, 391-407.
[110] H. L. Ko, E. C. Ren: Functional Aspects of PARP1 in DNA Repair and Tran-scription, Biomolecules, 2012, 2, 524-548.
[111] K. W. Caldecott: XRCC1 and DNA strand break repair, DNA Repair, 2003, 2, 955-969.
[112] H. E. Bryant; E. Petermann; N. Schultz, A. S. Jemth, O. Loseva, N. Issaeva, F. Johansson, S. Fernandez, P. McGlynn, T. Helleday: PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination, EMBO J.,2009, 28, 2601-2615 (modifizierte Abbildung).
[113] S. N. Khodyreva, R. Prasad, E. S. Ilina, M. V. Sukhanova, M. M Kutuzov, Y. Liu, E. W. Hou, S. H. Wilson, O I. Lavrik: Apurinic/apyrimidinic (AP) site recognition by the 50-dRP/AP lyase in poly(ADP-ribose) polymerase-1 (PARP-1), Proc. Natl. Acad. Sci. USA,2010, 107, 22090-22095.
[114] M. L. Hegde,T. K. Hazra, S. Mitra: Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells, Cell Res., 2008, 18, 27-47.
[115] E. Petermann, M. Ziegler, S. L. Oei: ATP-dependent selection between single nucleotide and long patch base excision repair, DNA Repair, 2003, 2, 1101-1104.
[116] S. B. De Lorenzo, A. G. Patel, R. M. Hurley, S. H. Kaufmann: The elephant and the blind men: making sense of PARP inhibitors in homologous recombination deficient tumor cells, Front. Oncol., 2013, 3, 1-12 (modifizierte Abbildung).
[117] J. R. Walker, R. A. Corpina, J. Goldberg: Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair, Nature, 2001,412, 607-614.
[118] J. M. Pleschke, H. E. Kleczkowska, M. Strohm, F. R. Althaus: Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins, J. Biol.
[118] J. M. Pleschke, H. E. Kleczkowska, M. Strohm, F. R. Althaus: Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins, J. Biol.