Inhibition of calf thymus type II DNA topoisomerase by poly(ADP-ribosylation).

Darby, Martyn K.; Schmitt, Bertram; Jongstra‐Bilen, Jenny; Vosberg, Hans−Peter

doi:10.1002/j.1460-2075.1985.tb03903.x

Cited by 119 publications

(38 citation statements)

References 35 publications

(19 reference statements)

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“…The apparent molecular masses of some of the poly(ADPribose) -nonhistone conjugates matched the molecular sizes of nuclear enzymes and other proteins that have previously been shown to function as acceptors for poly(ADP-ribose) in vitro: poly(ADP-ribose) synthase (1 10 kDa) [47 - (172 kDa) [30] as well as actin (43 kDa) [50]. The presence Fig.…”

Section: Identification Ofpoly(adp-ribose) Synthase and D N A Topoisomentioning

confidence: 54%

“…A frequent explanation is that poly(ADP-ribose) may regulate cellular events by directy modulating the enzymic activities of the modified proteins [5] in analogy to the action of extranuclear mono(ADP-ribosyl) transferases [3]. This view relies on the observation that poly(ADP-ribosy1)ation inhibits the activities of many nuclear enzymes in vitro: Ca2+/Mg2-dependent endonuclease [25], DNA ligases I and I1 [26,271, DNA topoisomerase I [28, 291 and 11 [30], DNA polymerase a and b [26], RNA polymerase I [32] and I1 [33], terminal deoxynucleotidyltransferase [26], ribonucleases [34] and poly(ADP-ribose) synthase itself [35]. An alternative model is based on the capacity of the poly(ADP-ribose) synthase to accumulate large amounts of negatively charged and possibly branched polymer chains at the site of the DNA break [36,371.…”

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confidence: 99%

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Poly(ADP-ribose) synthase is the major endogenous nonhistone acceptor for poly(ADP-ribose) in alkylated rat hepatoma cells

Adamietz

1987

Eur J Biochem

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The endogenous poly(ADP-ribosyl) -nonhistone protein conjugates were isolated from dimethyl-sulfatetreated rat hepatoma AH 7974 cells using aminophenylboronic-acid -agarose chromatography. Seven major components could be discerned on dodecyl sulfate gels (molecular mass 43,60,66, 86, 100, 110 and 170 kDa) while control cells indicated only slight staining at above 200 kDa. The most abundant conjugate formed in response to alkylation damage was further purified using preparative gel electrophoresis and identified on the basis of its intrinsic enzymic activity as automodified poly(APD-ribose) synthase. In addition, topoisomerase I activity was found associated with a 60-kDa peptide. ADP-ribosylated endonucleases and actin were not detectable. The purified conjugate fraction contained maximally 8.8 nmol/mg ADP-ribose and 7.9 nmol/mg oligo(ADPribose) with a mean chain length of 2.3 residues. The modifying (ADP-ribosyl), groups were attached to its acceptors by a hydroxylamine-insensitive bond and had practically no effect on the DNA affinity of either poly(ADP-ribose) synthase or topoisomerase I.Fragmentation of cellular DNA as induced by chemical or physical stress enhances the endogenous synthesis of poly(ADP-ribose) in the eucaryotic cell (for reviews see [l-31). The poly(ADP-ribose) synthase responsible for this reaction is capable of transferring the ADP-ribose moiety from the substrate NAD to a variety of chromosomal acceptor proteins with subsequent elongation to linear and branched homopolymers [4]. Formation of these products has been related to the regulation of several chromatin functions, especially those including intermediate nicking and resealing of DNA strands [5], such as cellular differentiation [6-91 and the DNA repair reactions [lo -131. The activity of the purified synthase was found to be completely dependent on binding to broken DNA [14] and inhibitors of the enzyme proved to be co-cytostatic [ l l , 15, 161 and co-carcinogenic [17-201 with DNA-damaging agents. These biological effects are apparently restricted to dividing cells, suggesting that poly(ADPribose) metabolism is required for the recovery of damaged cells progressing through the cell cycle but not for reactions directly involved in DNA excision repair [21,22]. Accordingly, inhibitors of poly(ADP-ribose) synthesis did not affect the rate of DNA ligation in alkylated HeLa cells [23,24] or mouse embryo fibroblasts [21], whereas strand-break frequency was enhanced and some breaks appeared to remain unrepaired in the absence of poly(ADP-ribose) synthesis. The molecular mechanism by which poly(ADP-ribose) can prevent alkylation-induced cell death ist still not understood. A frequent explanation is that poly(ADP-ribose) may regulate cellular events by directy modulating the enzymic activities of the modified proteins [5] in analogy to the action of extranuclear mono(ADP-ribosyl) transferases [3]. This view relies on the observation that poly(ADP-ribosy1)ation inhibits the activities of many nuclear enzymes in vitro: Ca2+/Mg2-dependent ...

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Section: Identification Ofpoly(adp-ribose) Synthase and D N A Topoisomentioning

confidence: 54%

mentioning

confidence: 99%

Poly(ADP-ribose) synthase is the major endogenous nonhistone acceptor for poly(ADP-ribose) in alkylated rat hepatoma cells

Adamietz

1987

Eur J Biochem

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“…their activity (Ferro and Olivera, 1984;Darby et al, 1985). Consistent with these observations Mattern et al (1987) demonstrated potentiation of camptothecin and teniposide cytotoxicity by the PARP inhibitor, 3-aminobenzamide (3AB), in L1210 cells.…”

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confidence: 67%

Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro

et al. 2001

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The potent novel poly(ADP-ribose) polymerase (PARP) inhibitor, NU1025, enhances the cytotoxicity of DNA-methylating agents and ionizing radiation by inhibiting DNA repair. We report here an investigation of the role of PARP in the cellular responses to inhibitors of topoisomerase I and II using NU1025. The cytotoxicity of the topoisomerase I inhibitor, camptothecin, was increased 2.6-fold in L1210 cells by co-incubation with NU1025. Camptothecin-induced DNA strand breaks were also increased 2.5-fold by NU1025 and exposure to camptothecin-activated PARP. In contrast, NU1025 did not increase the DNA strand breakage or cytotoxicity caused by the topoisomerase II inhibitor etoposide. Exposure to etoposide did not activate PARP even at concentrations that caused significant levels of apoptosis. Taken together, these data suggest that potentiation of camptothecin cytotoxicity by NU1025 is a direct result of increased DNA strand breakage, and that activation of PARP by camptothecin-induced DNA damage contributes to its repair and consequently cell survival. However, in L1210 cells at least, it would appear that PARP is not involved in the cellular response to etoposide-mediated DNA damage. On the basis of these data, PARP inhibitors may be potentially useful in combination with topoisomerase I inhibitor anticancer chemotherapy. © 2001 Cancer Research Campaign http://www.bjcancer.com

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“…Thus, poly(ADP) ribosylation decreases enzyme activity [50], whereas phosphorylation enhances catalytic-DNA turnover in vitru [51, 521. In eukaryotic cells, phosphorylation of topoisomerase I1 by a casein-kinase-11-like protein kinase is involved in controlling processes of cellular growth and the cell cycle [53,541.…”

Section: Discussionmentioning

confidence: 99%

A drug‐resistant variant of topoisomerase IIα in human HL‐60 cells exhibits alterations in catalytic pH optimum, DNA binding and sub‐nuclear distribution

Boege

Kjeldsen

Gieseler

et al. 1993

European Journal of Biochemistry

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Anion-exchange chromatography of partially purified human HL-60 topoisomerase IT resolves the known a (170 kDaj and / 3 (180 kDa) isoenzymes at 150 mM NaCl and 230 mh4 NaCl, respectively. An additional topoisomerase I1 fraction was eluted by > 300 mM NaCl. It could be identified by Western blotting as a late-eluting variant of topoisomerase IIa, which is functionally altered as compared to the early-eluting form, having the following properties: a shift in the catalytic optimum to pH 9 ; increased stability in DNA complex formation; approximately 100-fold resistance to orthovanadate ; approximately 1000-fold resistance to the cytostatic substances N-[4-(9-acridinylamino)-3-methoxyphenyl]-methanesulphonamide (amsacrine) and the podophyllotoxin etoposide (VP 16). 80% of the late-eluting topoisomerase IIa could be captured by SDS on calf thymus DNA without further enhancement by drugs. In contrast, the early-eluting topoisomerase IIa exhibits 10% complex formation with SDS alone, and an increase to 90% complex formation in the presence of drugs. A HL-60 subline (HL-60/R), approximately 1000-fold resistant to etoposide and amsacrine, has equivalent proportions of topoisomerase IIa and topoisomerase IIP and similar levels of both isoenzymes, as compared to the drug-sensitive HL-60/WT cells. However, determination of the cellular levels of the early-eluting and late-eluting forms of topoisomerase IIa revealed that the HLdO/R cell line contains approximately 80% of the late-eluting topoisomerase IIa, whereas the sensitive HL-60/WT cell line contains only 1 5 2 0 % of this form. The nuclear distribution of the two forms also differs. Sensitive HL-60/WT cells show a diffuse nuclear distribution but in resistant cells the distribution is localized in the nucleoli. Apparently two functionally distinct subforms of topoisomerase IIa coexist in drug-sensitive and drug-resistant HL-60 cells and changes in their relative levels affect the cellular sensitivity to topoisomerase-11-targeting drugs.Type I1 DNA topoisomerases are enzymes that regulate the topological state of DNA by a process in which DNA strands are passed through transient enzyme-bridged doublestranded DNA breaks. These enzymes appear to be closely related to chromosomal structures and are thought to play a crucial role in cellular processes such as DNA synthesis, -).Note. Dedicated to Professor Ernst J. M. Helmreich on the occasion of his 70th birthday. by separate genes. They differ in molecular mass (170 kDa and 180 kDaj, biochemical and pharmacological properties [8] and are differently expressed during the cell cycle and differentiation [5, 91. Type I1 topoisomerases have recently been identified as the cellular targets for a number of important antineoplastic agents. These include DNA-intercalating agents such as N-amide (amsacrine), doxorubicin and mitoxantrone, as well as agents that lack intercalating activity, such as etoposide and teniposide. The topoisomerase I1 mediated DNA strand breaks which are induced by these agents are thought to be respon...

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Inhibition of calf thymus type II DNA topoisomerase by poly(ADP-ribosylation).

Cited by 119 publications

References 35 publications

Poly(ADP-ribose) synthase is the major endogenous nonhistone acceptor for poly(ADP-ribose) in alkylated rat hepatoma cells

Poly(ADP-ribose) synthase is the major endogenous nonhistone acceptor for poly(ADP-ribose) in alkylated rat hepatoma cells

Differential effects of the poly (ADP-ribose) polymerase (PARP) inhibitor NU1025 on topoisomerase I and II inhibitor cytotoxicity in L1210 cells in vitro

A drug‐resistant variant of topoisomerase IIα in human HL‐60 cells exhibits alterations in catalytic pH optimum, DNA binding and sub‐nuclear distribution

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