Poly polymerase, activation

Zhuang, Z. X., Shen, Y., Shen, H. M., Ng, V. andOng, C. N. (1996). DNA strand breaks and poly(ADP-ribose) polymerase activation induced by crystalline nickel subsulfide in MRC-5 lung fibroblast cells, Human Exper. Toxicol., 15, 891-897. 

Decker P, Muller S (2002) Modulating poly (ADP-ribose) polymerase activity potential for the prevention and therapy of pathogenic situations involving DNA damage and oxidative stress. Curr Pharm Biotechnol 3 275-283... 

J. Z. Zhang, S. M. Henning, and M. E. Swendseid, Poly(ADP-ribose) Polymerase Activity and DNA Strand Breaks Are Affected in Tissues of Niacin-deficient Rats, J. Nutr. 123 (1993) 1349-55. 

Szabo G, Bahrle S. Role of nitrosative stress and poly(ADP-ribose) polymerase activation in myocardial reperfusion injury. Curr. Vase. Pharmacol. 2005 3 215-220. 

It has been recently reported34 that DNA polymerases of several oncogenic viruses are inhibited by ethidium bromide to different degrees according to the nature of the template used and the source of the enzyme. The effect of distamycin derivatives on the DNA polymerase activity of FL virions was therefore studied in the presence of poly (dA—dT), poly (dl dC) and poly (rA) (dT)g (Table 6). The DNA polymerase activity was found to be most sensitive to distamycin inhibition with poly (dA-dT) as primer-template and somewhat less so with poly (rA) (dT)g. In both cases the inhibitory response of the antibiotic increases according to the number of pyrrole rings in the molecule. With poly (dl - dC) as template no significant inhibition of DNA polymerase activity by distamycin derivatives was observed. 

Inhibition of DNA polymerase activity of MSV-M by distamycin A and its derivatives in the presence of various templates is shown in Table 7. The DNA-polymerase activities catalyzed by poly (dA-dT) and poly rA-(dT)g are very sensitive to distamycin action. The range of inhibitions by individual... 

Table 17 shows how template-dependent DNA polymerase activity of FLV is inhibited by various daunomycin derivatives. The reactions catalyzed by poly-(dA-dT) and poly (rA) (dT)i2 are highly sensitive to the action of daunomycin and its derivatives. Here again, daunomycin and adriamycin are most effective, and the N-acetyl derivative is completely inactive. It is interesting that the poly (dA-dT)-and poly (rA) (dT)i2-dependent reactions are more sensitive to these antibiotics than the endogenous reaction (see Table 17), while the DNA polymerase reaction catalyzed by poly (dl-dC) is completely insensitive. The most active derivatives (daunomycin, adriamycin and dihydro daunomycin) slightly stimulate 3H-dGMP incorporation catalyzed by poly (dl-dC). This stimulation is particularly noticeable in the case of dihydro daunomycin. Surprisingly, the N-acetyl derivative was found to inhibit this reaction. The mechanism of this inhibition is not understood. 

The inhibition of template-dependent DNA polymerase activity of MSV (M) by various daunomycin derivatives was also studied. Like the FLV system, the MSV poly (dA-dT)-and poly (rA) (dT)i2-dependent reactions were extremely sensitive to daunomycin derivatives. In both cases the N-acetyl derivative was completely ineffective. Again as with the FLV system, we found that the poly (dl-dC) - catalyzed incorporation of 3H-dGMP was not inhibited by any of the derivatives. In this system, unlike the FLV system, the N-acetyl derivative did not inhibit 3H-dGMP incorporation into DNA. Dihydro daunomycin here too greatly stimulated 3H-dGMP incorporation in the presence of poly (dl-dC).. 

Synthetic polymers containing either desoxyribonucleotide or ribonucleotide strands are known to stimulate the in vitro DNA synthesis by RNA tumor viruses. Some inhibitors of the DNA-polymerase reaction in RNA tumor viruses are known to exhibit a template-primer specificity6, 7 34 Table 22 shows the inhibition of template-dependent DNA polymerase activity of FLV by DEAE-F at various concentrations. The reaction catalyzed by poly (dl - dC) is most strongly stimulated by DEAE-F. Thus at 20 pg/reaction mixt. of DEAE-F the incorporation of 3H—dGMP is almost 4 times that of control. 

Fig. 23. Effects of thiolated polycytidylic acid (MPC) and unmodified polycytidylic acid (PC) on the DNA polymerase activities from MSV (Moloney) in the presence of poly rA-(dT)j4 ( ------ ) and poly (dA-dT) (O------O) as templates...

It is clear from these graphs that the modified polynucleotide, MPC, significantly inhibits the DNA polymerases present in both viral extracts furthermore, the inhibitory activity of MPC is very nearly the same in the two systems when poly (dA-dT) is used as the template (50% inhibition at 18 jxg/r.mix.), but in the presence of poly rA (dT)j4 as the template, MPC acts as a much more potent inhibitor of 3H-TMP incorporation in the MSV-M assay system (50% inhibition at 4 /rg/r.mix.) than in the FLV system (50% inhibition at 35 fig/r. mix.). In contrast, the unmodified polynucleotide, PC, stimulates DNA polymerase activity in both viral systems with poly (dA-dT) as the template, and it shows slight inhibitory activity (only 25 % inhibition, at 20-40 /ug/r.mix.) in the presence of the poly rA (dT)14 template. 

For HSV at least three mechanisms have been described that generate resistance to AC V deficiency or loss of viral TK activity, alteration in substrate specificity of the virus-encoded TK, and alteration in the substrate specificity of the viral DNA polymerase (1,8). Most of the ACVr mutants that have been isolated in vitro and recovered from clinical specimens are TK-deficient (TK). However, resistant clinical mutants that have an altered TK or altered DNA polymerase activity have occasionally been described too. Although TK mutants are crossresistant with drugs that also depend on viral TK for their activation (i.e., GCV, penciclovir and brivudin (BVDU), they remain sensitive to agents, such as PFA, vidarabine (Ara-A), and the acyclic nucleoside phosphonate (ANP) analogs. PFA, a pyrophosphate analog, is a direct inhibitor of the viral DNA poly-merase in which it binds to the site involved in releasing the pyrophosphate product of DNA synthesis. Phosphorylation of Ara-A to Ara-A triphosphate is carried out by cellular enzymes phosphorylation of ANP derivatives to their mono- and diphosphoryl derivatives is also carried out by cellular enzymes. 

Table 11.1 Effects of Various Compounds on Poly(ADP-ribose) Polymerase Activity"...

Mandir, A. S., Przedborski, S., Jackson-Lewis, V., Wang, A., Simbulan-Rosenthal, C. M., Smulson, M. E., et al. (1999) Poly(ADP-ribose) polymerase activation mediates l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Proc. Natl. Acad. Sci. USA 96, 5774-5779. 

The nonessential amino acid, L-alanine, has been reported to compete with tryptophan binding to hepatic nuclei in vitro.174485 However, L-alanine is not capable of stimulating hepatic protein synthesis as does L-tryptophan.185 Yet, L-alanine in competing with L-tryptophan for nuclear receptor binding is able to diminish or negate L-tryptophan s ability to stimulate hepatic protein synthesis.185 Similarly, DL- 3(l-naphthyl)alanine is capable of acting like L-alanine.173 Also, L-alanine inhibited elevations of other rapidly induced metabolic reactions, such as nuclear RNA efflux and nuclear poly(A)polymerase activity, which occurred due to L-tryptophan alone. These two stimulatory... 

Kurl, R. N., Holmes, S. C., Verney, E., and Sidransky H., Nuclear envelope glycoprotein with poly(A) polymerase activity of rat liver Isolation, characterization, and immunohistochemical localization, Biochemistry 27[25], 8974,1988. 

Increased NO exerts cellular toxicity primarily by depleting energy stores through multiple mechanisms (I) by prolonging poly-(ADP-ribose)polymerase activation... 

Szabo, E. et al., Peroxynitrite production, DNA breakage, and poly(ADP-ribose) polymerase activation in a mouse model of oxazolone-induced contact hypersensitivity, J. Invest. Dermatol, 117(1), 74, 2001. 

Rippmann JF, Damm K, Schnapp A. Functional characterization of the poly(ADP-ribose) polymerase activity of tankyrase 1, a potential regulator of telomere length. J Mol Biol 2002 323(2) 217-24. 

Grube K, Burkle A. Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span. Proc Nad Acad Sci USA 1992 89 11759-63. 

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