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Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut
Received December 17, 2007; accepted March 18, 2008
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Abstract |
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, 1996, 2002; Champoux, 2001; Pourquier and Pommier, 2001). Relaxation of DNA by topoisomerase I involves four catalytic steps: 1) DNA binding, 2) cleavage with the formation of topoisomerase I-linked DNA (TLD) complex, 3) strand rotation, and 4) religation. Once topoisomerase I binds to the DNA, it creates a transient DNA break, by the formation of a covalent tyrosyl phosphodiester bond with the 3' end of DNA. After the DNA is relaxed, topoisomerase I religates the cleaved DNA. This cleavage-religation coupling, which is important for cell function, can be disrupted by topoisomerase I poisons, such as camptothecin and topotecan (Lorence and Nessler, 2004; Thomas et al., 2004; Sriram et al., 2005; Pommier, 2006). Even though stabilization of the TLD complex, induced by camptothecin, is not sufficient to cause cell death, the stabilized TLD has the potential of being converted to double-strand DNA breaks, which can lead to cell death (Hsiang et al., 1989; Wu and Liu, 1997; Liu et al., 2000). The religation of TLD is therefore critical in the process.
PARP-1 is a highly conserved nuclear enzyme that plays diverse roles in many molecular and cellular processes, including DNA damage detection and repair, chromatin modification, transcription, cell death pathways, insulator function, and mitotic apparatus function (Ivana Scovassi and Diederich, 2004; Bürkle et al., 2005; Kim et al., 2005; Meyer-Ficca et al., 2005; Oei et al., 2005; Strosznajder et al., 2005). It has been known to modulate the toxicity of camptothecin by catalyzing the polymerization of ADP-ribose units from NAD molecules to target proteins, including topoisomerase I and PARP-1 (Chatterjee et al., 1989; Beidler et al., 1996; Bürkle, 2005). We reported previously that PARP-1 could destabilize the TLD complex, and hence promote religation either by direct interaction with topoisomerase I or by the formation of poly(ADP-ribosyl)ated topoisomerase I in the presence of NAD. Furthermore, ATP was found to be a potential regulator for the camptothecin action by inhibiting the activity of PARP-1/NAD on topoisomerase I (Park and Cheng, 2005).
The effect of ATP and other nucleoside analogs on topoisomerase I activity has been studied (Rowe et al., 1981; Foglesong and Bauer, 1984; Goto et al., 1984; Low and Holden, 1985; Castora and Kelly, 1986; Shaffer and Traktman, 1987; Chen and Castora, 1988; Liu et al., 1989; Sekiguchi and Shuman, 1994; Stewart et al., 1996; Chen and Hwang, 1999). ATP inhibited the activity of topoisomerase I from human leukemia cells (Castora and Kelly, 1986; Liu et al., 1989), HeLa cells (Low and Holden, 1985), and Ustilago maydis (Rowe et al., 1981). However, ATP did not inhibit the activity of topoisomerase I from yeast (Goto et al., 1984) at concentrations up to 5 mM. Foglesong and Bauer (1984) and Sekiguchi and Shuman (1994) demonstrated that ATP could promote the DNA relaxation activity of topoisomerase I from vaccinia virus, whereas, Shaffer and Traktman (1987) observed that the activity of topoisomerase I, isolated from vaccinia virus cores, was inhibited by ATP. Despite these conflicting observations, it is generally agreed that the DNA relaxation activity can be inhibited by ATP.
The mechanism of the inhibitory activity is unclear. Stewart et al. (1996) claimed that ATP inhibits topoisomerase I activity by lowering the free Mg2+ concentration, which is essential for the enzyme activity. However, Chen and Hwang (1999) reported that the inhibition of topoisomerase I activity was Mg2+-independent. ATP was also shown to have direct impact on topoisomerase I and PARP-1. ATP inhibits PARP-1 autopoly(ADP-ribosyl)ation (Kim et al., 2004; Kun et al., 2004) as well as poly(ADP-ribosyl)ation of DNA-dependent protein kinase catalytic subunit (Ariumi et al., 1999) and topoisomerase I (Park and Cheng, 2005). An ATP binding site was identified within the C-terminal domain of topoisomerase I for its kinase activity (Rossi et al., 1996, 1998), even though topoisomerase I does not need ATP as a cofactor or an energy source for its DNA relaxation activity. However, the role of the direct interaction between ATP and topoisomerase I in the regulation of DNA relaxation activity is still unknown.
In the present study, we investigated the mechanism of action of ATP on PARP-1/NAD facilitated-TLD religation. Our data reveal the possible role of ATP in the regulation of topoisomerase I activity, in the presence of camptothecin and topotecan, through the direct interaction with PARP-1 and topoisomerase I.
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Materials and Methods |
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Recombinant Proteins. Full-length human topoisomerase I was expressed in Sf-9 cells, and it was purified as described previously (Park and Cheng, 2005). Human recombinant PARP-1 was purchased from Trevigen (Gaithersburg, MD).
Oligonucleotides. Oligonucleotides were synthesized by Integrated DNA Technologies, Inc. (Coralville, IA), and the sequences are as follow: ON4, 5'-pTAAAAATTTTTCCAAGTCTTTTTTC-3'; ON5, 5'-GAAAAAAGACTTGG-3'; and ON6, 5'-GGAAAAATTTTTA-3'. ON5 was 5' end-labeled with [
-32P]ATP using T4 polynucleotide kinase (New England Biolabs, Ipswich, MA), and it was annealed to ON4 to generate a duplex oligonucleotide substrate, as described previously (Park and Cheng, 2005).
Oligonucleotide Cleavage Reaction. Topoisomerase I (220 fmol) and radiolabeled ON5-ON4 oligoduplex (
50 fmol) were incubated in the presence or absence of nucleotide in a 10-µl reaction containing 10 mM Tris-HCl, pH 7.5, 50 mM KCl, 5 mM MgCl2, 0.1 mM EDTA, and 30 µg/ml bovine serum albumin. The reaction was performed at 37°C for 15 min, and it was stopped by adding SDS to the final concentration of 0.5%. Covalent-linked topoisomerase I was digested by trypsin (0.2 mg/ml final concentration) at 37°C for 30 min, and 5 µl of loading buffer (98% formamide, 10 mM EDTA, 10 mM NaOH, 0.1% bromphenol blue, and 0.1% xylene cyanol) was added, boiled, and separated on a 20% denaturing urea/polyacrylamide gel electrophoresis. The gel was analyzed by autoradiography and PhosphorImaging screen (GE Healthcare). Alternatively, reactions were stopped by adding Laemmli loading buffer without digestion. Covalent complexes of topoisomerase I with cleaved oligonucleotides were separated from the uncleaved substrates by SDS-polyacrylamide gel electrophoresis and visualized by autoradiography.
Oligonucleotide Religation Reaction. Religation reaction was initiated with the suicide cleavage complex, generated by a cleavage reaction by adding 5 pmol of ON6 alone or with components such as PARP, NAD, or nucleotides. The reaction was performed at 37°C for 30 min and analyzed by 20% urea/polyacrylamide gel electrophoresis, as described above, except that TLD was digested by 1 mg/ml proteinase K at 37°C for 1 h.
Plasmid Relaxation Assay. The reactions were carried out in a buffer containing 0.25 µg of supercoiled pUC18, 220 fmol of topoisomerase I, 10 mM Tris-HCl, pH 7.5, 50 mM KCl, 5 mM MgCl2, 0.1 mM EDTA, 5% glycerol, and 30 µg/ml bovine serum albumin. The reactions were incubated for 30 min at 37°C, and then they were terminated by the addition of 1% SDS. DNA was then separated in a 1% agarose gel with or without ethidium bromide at 0.25 µg/ml. To study the conversion of nicked DNA to the relaxed form by PARP-1/NAD, the reactions were performed in the presence of 40 µM camptothecin before the addition of 21.5 fmol of PARP-1 and 18.2 µM NAD. The reactions were then continued for another 30 min at 37°C.
Immunoprecipitation Assay. Religation reactions were performed, followed by the incubation with anti-PAR antibody (Trevigen) and protein G Plus/protein A agarose (Calbiochem, San Diego, CA). Supernatants were collected, and immunoprecipitates were washed five times with 10 mM Tris-HCl, pH 7.5, 50 mM KCl, 5 mM MgCl2, 0.1 mM EDTA, 150 mM NaCl, and 1% Triton X-100. Samples were electrophoresed on 7.5% acrylamide gel and analyzed by Western blot analysis using anti-topoisomerase I antibody (clone 21, generated by our laboratory), as described previously (Park and Cheng, 2005).
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Results |
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; Park and Cheng, 2005), cleavage products (12-mer oligonucleotides containing amino acid residues of topoisomerase I) migrated slower than the substrate (14-mer). Figure 1A showed that ATP, UTP, CTP, and GTP, up to concentrations of 4 mM, did not have a significant effect on the cleavage process.
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We also studied the impact of nucleoside triphosphates on the formation of TLD. Instead of digesting with trypsin, the covalent complexes of topoisomerase I with cleaved oligonucleotides were separated from the uncleaved substrates by SDS-polyacrylamide gel electrophoresis. Figure 1B showed that the nucleoside triphosphates did not interfere with the TLD formation. Our data therefore suggest that the four nucleoside triphosphates have no effect on the DNA binding and cleavage activities of topoisomerase I.
Impact of Nucleoside Triphosphates on Topoisomerase I Religation Activity. After DNA cleavage, relaxation of DNA by topoisomerase I is known to be completed by the religation process. The effect of nucleoside triphosphates on topoisomerase I-facilitated DNA religation was studied by the addition of a complementary 13-mer (ON6) to the suicide cleavage complex, which was obtained in the cleavage reaction. ON6 quickly religated with ON5 (12-mer) in the presence of topoisomerase I, and it resulted in the formation of the 25-mer religation product (Fig. 2A). The four nucleoside triphosphates ATP, UTP, CTP, and GTP, at up to 4 mM concentration, did not interfere with the TLD religation process (Fig. 2B).
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Inhibition of PARP-1/NAD-Facilitated Religation Action of Topoisomerase I by ATP in the Presence of Camptothecin Does Not Require ATP Hydrolysis. We have previously demonstrated that PARP-1/NAD-facilitated TLD religation in the presence of camptothecin, whereas ATP reversed the action of PARP-1/NAD (Park and Cheng, 2005). Relaxation assay revealed that ATP could inhibit the PARP-1/NAD-mediated religation of camptothecin-induced nicked plasmid DNA (Fig. 3A). Camptothecin stabilized the TLD complex and resulted in the formation of nicked DNA, which was religated in the presence of PARP-1/NAD (Fig. 3A, bottom). Increase of nicked DNA level was observed with up to 2 mM ATP in a dose-dependent manner. This is consistent with our previous finding that ATP inhibited the action of PARP-1/NAD. In the oligonucleotide religation assay, 2 mM ATP was found to suppress up to 90% of the religation activity of TLD in the presence of PARP-1/NAD and camptothecin analogs (Fig. 3B, top). To examine whether ATP hydrolysis was required for the inhibition of PARP-1/NAD-facilitated topoisomerase I religation activity, the impact of AMP-PNP, which is an ATP analog that prevents hydrolysis of the phosphate bond, was studied. Figure 3B (bottom) indicated that AMP-PNP could also inhibit the PARP-1/NAD action at a relatively lower potency, compared with ATP. This suggests that ATP hydrolysis is not essential for the inhibitory activity of ATP. The structure, however, could be a critical factor that determines the potency of nucleotides. The effect of ATP and AMP-PNP was found to be biphasic. Regaining of religation activity was observed at higher concentrations of nucleotides (>3 and >8 mM ATP and AMP-PNP, respectively).
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). To investigate whether ATP inhibits poly(ADP-ribosyl)ation of topoisomerase I, religation reaction was performed with cold (unlabeled) ON6 13-mer in the presence of ATP. Anti-PAR immunoprecipitate, as well as the supernatant collected before and after the religation reaction, was probed with topoisomerase I antibody. The result showed that poly(ADP-ribosyl)ation of topoisomerase I decreased in a dose-dependent manner with increasing ATP at concentrations up to 4 mM (Fig. 4A). This suggests that suppression of PARP-1 activity by 
2 mM ATP may account for, at least in part, the inhibitory effect on the religation. A low level of poly(ADP-ribosyl)ation was detected in the presence of 0.4 mM ATP, at which TLD religation was drastically inhibited (Fig. 3). This indicates that suppression of TLD religation may not require complete blockage of PARP-1 activity. It is noteworthy that poly(ADP-ribosyl)ation of topoisomerase I was found to be almost completely suppressed by 4 mM ATP, at which we observed an increase in TLD religation activity (Fig. 3). This implies that ATP at higher concentrations could promote the religation process by a different mechanism that is independent of PARP-1.
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To understand the nature of ATP inhibition on PARP-1/NAD-facilitated TLD religation activity, a kinetic analysis was performed by running religation reactions with various concentrations of ATP in the presence of camptothecin, PARP-1, and various concentrations of NAD at 37°C for 30 min. The double-reciprocal plot showed that ATP dose-dependently decrease Km, app, but that it has no effect on Vmax, suggesting that ATP is a competitive inhibitor of PARP-1 with respect to NAD for the facilitation of topoisomerase I religation in the presence of camptothecin (Fig. 4B). The Km value of the PARP-1/NAD action on topoisomerase I religation was 7.7 ± 1.5 µM. Replotting Km, app against [ATP]2 revealed a linear relationship in which the Ki,app value was 90 ± 6.0 µM.
Inhibition on PARP-1/NAD-Facilitated Topoisomerase I Religation by Nucleotides Could Be Structure-Specific. Although hydrolysis of ATP is not essential for its inhibitory activity, the chemical structure seems to determine the potency of the inhibition on TLD religation activity facilitated by PARP-1/NAD. Comparison of nucleotide analogs with different numbers of phosphate groups revealed that both ATP and ADP were almost equally potent against the religation (EC50 0.25 and 0.3 mM, respectively), whereas AMP exhibited the weakest inhibition (EC50 2 mM). The two phosphate groups could therefore be critical for the inhibitory activity of ATP.
The importance of the sugar moiety of nucleotides was examined by comparing ATP, dATP, ddATP, and 2'-ara-ATP, which has an arabinose instead of a ribose. The religation activity was found to be less susceptible to the action of 2'-ara-ATP (EC50 1 mM) (Fig. 5B). The presence of the deoxy- or dideoxyribose moiety in dATP or ddATP caused a significant decrease in the potency of inhibition (EC50 1.8 and 1.6 mM, respectively), compared with ATP. The result suggests that the structure of the sugar moiety is critical for the inhibition.
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Three naturally occurring diadenosine polyphosphates, Ap3A, Ap4A, and Ap5A, were also found to inhibit religation, whereas no significant difference in potency was observed among the three analogs (Ogilvie et al., 1996; McLennan, 2000) (Fig. 5F). Their EC50 values fell within the concentration range from 0.6 to 1.0 mM. A maximum inhibition of up to 60% on the religation activity was observed with these compounds at concentrations of 2 mM or higher (data not shown).
Because CTP showed strong activity comparable with that of ATP, several cytidine analogs were examined. CDP-choline is a naturally occurring metabolite, which has a choline group instead of a -phosphate, and it is essential for the synthesis of phosphatidylcholine, one of the cell membrane components (Fioravanti and Yanagi, 2005). CDP-choline inhibited PARP-1/NAD action on the religation activity of topoisomerase I in the presence of camptothecin at a lower potency (EC50 1.5 mM) compared with CTP (EC50 0.3 mM) (Fig. 5G). Decrease in the potency of diadenosine polyphosphates and CDP-choline, compared with ATP and CTP, respectively, indicates that modification of the terminal phosphate group may interfere with the interaction between nucleotides and PARP-1. In addition, metabolites of two anticancer nucleoside analogs, gemcitabine triphosphate, which has two fluorines in the 2' position of the ribose, and troxacitabine triphosphate, which is an L-configuration nucleoside with a dioxolane sugar moiety, did not show significant effect on the religation (1 and 3% inhibition, respectively) at a concentration of 0.4 mM.
Taken together, our findings suggest that the inhibition of PARP-1/NAD-facilitated TLD religation by nucleotides at up to 2 mM could be structure-specific. The base, the sugar, and the phosphate group could be critical for the action.
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Discussion |
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). The present study demonstrates the multiple actions of ATP on the religation of TLD by interacting with PARP-1 and topoisomerase I.
Poly(ADP-ribosyl)ated topoisomerase I was reported to exhibit lower DNA relaxation activity (Ferro et al., 1983; Jongstra-Bilen et al., 1983). Our previous findings (Park and Cheng, 2005) as well as those of the present study, however, provide evidence for the enhancement of TLD religation activity by the modification. This indicates that poly(ADP-ribosyl)ation could lower the binding affinity of topoisomerase I to the DNA. This could account for the low relaxation activity of the purified poly(ADP-ribosyl)ated topoisomerase I observed by others. However, once the TLD complex is formed, poly(ADP-ribosyl)ation of topoisomerase I could facilitate the disassembling of topoisomerase I from the DNA and hence allow religation to occur.
In the absence of PARP-1/NAD, ATP inhibition of DNA relaxation activity has been well known, as reported by us and by others previously. However, it is not clear which catalytic step(s) is inhibited. In this study, we showed that ATP had no effect on oligonucleotide cleavage and religation activities of topoisomerase I. Our finding is consistent with the report by Chen and Castora (1988), who observed that ATP did not interfere with the binding and cleavage activity of topoisomerase I. We postulate that among the four catalytic steps of topoisomerase I, it is the strand rotation step that serves as the target for ATP (Rowe et al., 1981; Castora and Kelly, 1986).
In the presence of PARP-1/NAD, ATP inhibits TLD religation by competing with NAD for PARP-1 binding and thus suppresses poly(ADP-ribosyl)ation of topoisomerase I, as well as auto-poly(ADP-ribosyl)ation of PARP-1. This may lead to a decrease in the religation activity of TLD (Kun et al., 2004; Park and Cheng, 2005). It was reported that the mode of inhibition by ATP was noncompetitive with respect to NAD in autopoly(ADP-ribosyl)ation of PARP-1 (Kun et al., 2004). This indicates the possibility of the presence of two ATP binding sites of similar binding affinity on PARP-1, which is supported by our finding that the Km,app is directly proportional to the square of the ATP concentration. However, it is also possible that conformational changes of topoisomerase I, induced by ATP, could make topoisomerase I more resistant to poly(ADP-ribosyl)ation by PARP-1/NAD. This mechanism cannot be ruled out at this time.
The interaction of nucleoside triphosphates with PARP-1/NAD could be structure-specific. Changes of the base, the sugar, or the phosphate group of the nucleotide modulate the potency of the TLD religation activity. The activity of topoisomerase I seems to be more susceptible to the action of nucleotide triphosphates with the NH2 group on the bases (i.e., ATP and CTP). In addition, nucleotides with two or more phosphate groups (i.e., ADP and ATP) were found to have a more potent effect on the religation activity of topoisomerase I. We suspect that nucleotides that are structurally similar to NAD (which possesses two phosphate groups and the NH2 group on the nucleoside) could be stronger competitors with respect to NAD for the binding site(s) on PARP-1.
Direct interaction of topoisomerase I with ATP has been reported to be critical for its activity (Rossi et al., 1996, 1998). Besides the inhibitory effect of the nucleotide analogs described above, we also observed an additional effect on the religation activity of topoisomerase I. ATP and CTP, at 410 mM, reversed the inhibitory effect on the TLD religation activity in the presence of camptothecin analogs. The detailed mechanism of action by which ATP and CTP destabilize the TLD complex is not clear. Because high-performance liquid chromatography analysis showed that ATP did not affect the stability of camptothecin (data not shown), the reversal action observed here could be due to the facilitation of topoisomerase I religation activity. It is conceivable that conformational changes of topoisomerase I, induced by ATP or CTP, could lead to the increase of DNA religation in the presence of camptothecin analogs. Direct interaction of ATP with topoisomerase I was shown to be a prerequisite for the phosphorylation of the SR protein by topoisomerase I (Rossi et al., 1996, 1998). It is reasonable to postulate that all the nucleotides could interact with topoisomerase I through the same ATP binding site; however, it is also possible that topoisomerase I has additional binding sites for the nucleotide. The binding of nucleotides to topoisomerase I could be structure-specific.
Desensitization of camptothecin inhibitory action on the religation activity of topoisomerase I by ATP and CTP, but not by UTP and GTP, revealed that the NH2 group of adenine or cytosine could be required in the binding of nucleoside triphosphates to topoisomerase I in the promotion of TLD religation. In addition, ADP and AMP, at up to 4 mM concentrations, did not increase the religation activity of topoisomerase I in the presence of camptothecin (data not shown). It is likely that the presence of three phosphates, instead of two or fewer phosphates, is critical for the reversal action. This also implies that different ATP binding sites could be responsible for the differential effects on the religation process.
Modulation of PARP-1 has been suggested to be a strategy to potentiate the chemotherapeutic action of topoisomerase I poisons (Chatterjee et al., 1989; Cimmino et al., 2007). We anticipate that nuclear ATP, as well as several naturally occurring nucleoside analogs, could play a key role in determining the effectiveness of camptothecin analogs in causing double-strand breaks, which leads to cell death. In essence, the alteration of intracellular ATP levels could interfere with PARP-1 activity and result in cells displaying different sensitivities to this class of topoisomerase I poisons. It is noted that the nuclear concentration of ATP, which is similar to that in the cytosol, is in the range of 110 mM (Miller and Horowitz, 1986; Jiang et al., 1998; Gajewski et al., 2003; Smith et al., 2005). Based on our in vitro findings, at these concentrations, PARP-1 activity was supposed to be inhibited by ATP in a competitive manner. The presence of the intrinsic PARP-1 activity in cells indicates that the regulation is probably dependent on the relative ratio of NAD/ATP, instead of the ATP pool size, because ATP is a competitive inhibitor with respect to NAD. In addition, ATP compartmentation may play a role in the regulation of PARP-1.
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Acknowledgements |
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Footnotes |
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S.-Y.P. and C.-H.L. contributed equally to this work.
ABBREVIATIONS: TLD, topoisomerase I-linked DNA; PARP, poly(ADP-ribose) polymerase; ApnA, diadenosine polyphosphate; adenyl-5'-yl imidodiphosphate; 2'-ara-ATP, 2'-9β-D-arabinofuranosyladenine 5'-triphosphate; ON, oligonucleotide; PAR, poly(ADP-ribose); camptothecin; TPT, topotecan.
1 Current affiliation: Korea Institute of Toxicology, Yuseong, Daejeon, Korea. 
2 Current affiliation: Department of Chemistry, The University of Hong Kong, Hong Kong.
Address correspondence to: Dr. Yung-Chi Cheng, Department of Pharmacology, Yale University School of Medicine, P.O. Box 208066, New Haven, CT 06520-8066. E-mail: yccheng{at}yale.edu.
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