Poly adenosine 5 -

Over production of NO can lead to mutagenesis and cell death and has been shown to be mutagenic in a variety of systems [40]. These range from mutations in E. coli and human cell lines [39] to an in vivo mouse model [127]. Using cell lines as an in vitro model of NO toxicity, a range of pathways have been identified from inhibition of DNA synthesis, mitochondrial damage, apoptosis, cell cycle distribution changes and DNA strand breaks [128]. An effect on ribonuclease reductase activity has also been shown, which seemed only to be temporary in nature and the activation of poly(adenosine 5 -di-phosphoribose) synthetase has also been attributed to both NO and ONOO" [129]. 

Poly (adenosine 5 -diphosphate ribose) polymerase-1 (PARP-1) [also known as poly (ADP-ribose) synthetase, PARS E.C. 2.4.2.30] is a chromatin-bound enzyme, which is abundantly present in the nuclei of numerous cell types. Single strand breaks in DNA trigger the aaivation of PARP-1, which transfers ADP-ribose moieties from nicotinamide adenine dinucleotide (NAD ) to various nuclear proteins including histones and PARP (automodification domain) itself. This reaaion leads to the generation of nicotinamide, which is an inhibitor (negative feedback) of PARP-1 aaivity. Continuous or excessive activation of PARP-1 (and perhaps other, less well charaaerized members of the PARP enzyme family) produces extended... 

Wayman NS, McDonald MC, Thompson AC et al. 5-Aminoisoquinolinone, a potent inhibitor of poly (adenosine 5 diphosphate ribose) polymerase, reduces myocardial infarct size. Eur J Pharmacol... 

Thiemermann C. Development of novel, water-soluble inhibitors of poly (adenosine 5 -diphosphate ribose) synthetase activity for use in shock and ischemia-reperfusion injury. Crit Care Med 2002 30 11.63-1165. 

Delaney CA, Wang LZ, Kyle S, White AW, Calvert AH, Curtin NJ, Durkacz BW, Hostomsky Z, Newell DR (2000) Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly(adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines. Clin Cancer Res 6 2860-2867... 

This enzyme [EC 2.4.2.30] (also referred to as NAD+ ADP-ribosyltransferase, poly(ADP) polymerase, poly-(adenosine diphosphate ribose) polymerase, and ADP-ribosyltransferase (polymerizing)) catalyzes the reaction of NAD+ with [ADP-D-ribosyl] to produce nicotinamide and [ADP-D-ribosyl]( + i). The ADP-d-ribosyl group of NAD+ is transferred to an acceptor carboxyl group on a histone or on the enzyme itself, and further ADP-ribosyl groups are transferred to the 2 -position of the terminal adenosine moiety, building up a polymer with an average chain length of twenty to thirty units. 

I The first and simplest of them are those of sperm-head nucjeo-protein [17]. Here the nucleic acid, DNA, seems to determine the structure. In the gap already mentioned between the coils of the double spiral there is no room for any more nucleotide, but only for the smaller protamine chain, as Wilkins has shown. No similar structure has been found for natural RNA but it does occur for the combination of two different artificial poly-adenosine ribose phosphate and guanine ribose phosphate. This fact, established by Rich [18], is the best example of heterogeneous mutual coiling in vitro of polymer molecules. 

Jump, D.B. and Smulson, M. (1980) Purification and characterization of the major non-histone protein acceptor for poly (adenosine diphosphate ribose) in HeLa cell nuclei. Biochemistry, 19, 1024-1030. 

The Bl subsite is responsible for the pyrimidine specificity of RNase A. RNase A cleaves poly(cytidine) [poly(C)] or poly (uridine) [poly(U)] lO -fold faster than poly(adenosine) [poly(A)] as a result of the selectivity of the Bl... 

Miwa M, Sugimura T. Splitting of the ribose-ribose link e of poly(adenosine diphosphate-robose) by a calf thymus extract. J Biol Chem 1971 246 6362-4. 

Panzeter PL, Realini C, Althaus FR. Noncovalent interactions of poly(adenosine diphosphate ri-bose) with histones. Biochemistry 1992 31 1379-1385. 

Malik N, Smulson M. A relationship between nuclear poly(adenosine diphosphate tibosylation) and acetylation postttanslational modifications. Biochemistry 1984 23 3721-3725. 

Jonsson GG, Jacobson EL, Jacobson MK. Mechanism of alteration of poly(adenosine diphosphate-ribose) metabolism by hyperthermia. Cancer Res 1988 48(15) 4233-9. 

Scott GS, Jakeman LB, Stokes BT et al. Peroxynitrite production and activation of poly (adenosine diphosphate-ribose) synthetase in spinal cord injury. Ann Neurol 1999 45(1) 120-4. 

Tabuchi K, Ito Z, Tsuji S et al. Poly(adenosine diphosphate-ribose) synthetase inhibitor 3-aminobenzamide alleviates cochlear dysfunction induced by transient ischemia. Ann Otol Rhinol Laryngol 2001 110(2) 118-21. 

Yoshihara K, Tanigawa Y, Koide SS. Inhibition of rat liver Ca2+, Mg2+-dependent endonuclease activity by nicotinamide adenine dinucleotide and poly (adenosine diphosphate ribose) synthetase. Biochem Biophys Res Common 1974 59(2) 658-665. 

Watson A], Askew JN, Benson RS. Poly(adenosine diphosphate ribose) polymerase inhibition prevents necrosis induced by H202 but not apoptosis. Gastroenterology 1995 109(2) 472-482. 

Bozlu M, Eskandari G, Cayan S et al. The effect of poly (adenosine diphosphate-ribose) polymerase inhibitors on biochemical changes in testicular ischemia-reperfusion injury. J Urol 2003 169 1870-1873. 

Zingarelli B, O Connor M, Wong H et al. Peroxynitrite-mediated DNA strand breakage activates poly-adenosine diphosphate ribosyl synthetase and causes cellular eneigy depletion in macrophages stimulated with bacterial lipopolysaccharide. J Immunol 1996 156 350-8. 

Okolie EE, Shall S. The significance of antibodies to poly(adenosine diphosphate-ribose) in systemic lupus erythematosus. Clin Exp Immunol 1979 36 151-64. 

Yama ami T, Miwa A, Takasawa S et al. Induction of rat pancreatic B-cell tumors by the combined administration of streptozotocin or alloxan and poly(adenosine diphosphate ribose) synthetase inhibitors. Cancer Res 1985 45(4) 1845-1849. 

Milam MK, Cleaver EJ. Inhibitors of poly (adenosine diphosphate-ribose) sjmthesis Effect on other metabolic processes. Science 1984 223 589-591. 

The poly-adenosine diphosphate-ribose polymerase (PARP) (Table II) was essential for DNA repair in ancient fungi and remains in use in Aspergillus and Neurospora species. The PARP protein interacts with the entire protein metabolism (catalytic activities) of the cell in a stimulatory fashion. Haploid fungal cells with defective PARP die diploid cells survive, but undergo increased mutational events. In one case, loss-of-function phosphatases fail to deactivate MAPK, resulting in hyphal hyperprolifreation (Figure 63). Human cancer cells use PARP to initiates... 

Nishizuka Y, Ueda K, Honjo T, Hayaishi 0 (1968) Enzymic adenosine diphosphate ribosyla-tion of histone and poly(adenosine diphosphate ribose) synthesis in rat liver nuclei. J Biol Chem 243 3765-3767... 

Niedergang C, Okazaki H, Mandel P (1979) Properties of purified calf thymus poly(adenosine diphosphate ribose) polymerase. Comparison of the DNA-independent and the DNA-dependent enzyme. Eur J Biochem 102 43-57... 

Okazaki H, Niedergang C, Mandel P (1980) Adenosine diphosphate ribosylation of histone HI by purified calf thymus poly adenosine diphosphate ribose polymerase. Biochimie 62 147-157... 

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