Local base sequence preferences for DNA cleavage by mammalian topoisomerase II in the presence of amsacrine or teniposide

Pommier, ﻿Yves; Capranico, Giovanni; Orr, Ann; Kohn, Kurt W.

doi:10.1093/nar/19.21.5973

Cited by 128 publications

(111 citation statements)

References 19 publications

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“…3 and Table I). This result agrees well with previous analyses (18,29). Preference on the opposite strand showed a complementary (although slightly weaker) preference for G at position ϩ5.…”

Section: Different Base Preferences Of Amsacrine-and Mitoxantronestabsupporting

confidence: 93%

“…4 and Table I), the human enzyme showed a clear preference for A ϩ1 (47 of 64 sites) and a complementary (although weaker) preference for T ϩ4 (28 of 64 sites), which conforms with earlier studies (29,33,34). The yeast protein also demonstrated a strong preference for A ϩ1 (29 of 61 sites) but an additional preference for T at position Ϫ1 (32 of 61 sites) as well as the complementary A at position ϩ5 (28 of 61 sites), which was not seen in the human enzyme.…”

Section: Different Base Preferences Of Amsacrine-and Mitoxantronestabsupporting

confidence: 92%

“…Early studies showed that topoisomerase-targeting drugs influence the sequence specificity of DNA cleavage by top2 compared with sites of DNA cleavage in the absence of drugs (28,29,39). Not surprisingly, drugs that bind DNA in the absence of enzyme most commonly resulted in cleavage specificities that differed from that seen with the enzyme in the absence of drug.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Analysis of Yeast and Human Type II Topoisomerases

Strumberg

Nitiss²,

Dong³

et al. 1999

Journal of Biological Chemistry

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The DNA sequence selectivity of topoisomerase II (top2)-DNA cleavage complexes was examined for the human (top2␣), yeast, and Escherichia coli (i.e. gyrase) enzymes in the absence or presence of anticancer or antibacterial drugs. Species-specific differences were observed for calcium-promoted DNA cleavage. Similarities and differences in DNA cleavage patterns and nucleic acid sequence preferences were also observed between the human, yeast, and E. coli top2 enzymes in the presence of the non-intercalators fluoroquinolone CP-115,953, etoposide, and azatoxin and the intercalators amsacrine and mitoxantrone. Additional base preferences were generally observed for the yeast when compared with the human top2␣ enzyme. Preferences in the immediate flanks of the top2-mediated DNA cleavage sites are, however, consistent with the drug stacking model for both enzymes. We also analyzed and compared homologous mutations in yeast and human top2, i.e. Ser 740 3 Trp and Ser 763 3 Trp, respectively. Both mutations decreased the reversibility of the etoposide-stabilized cleavage sites and produced consistent base sequence preference changes. These data demonstrate similarities and differences between human and yeast top2 enzymes. They also indicate that the structure of the enzyme/DNA interface plays a key role in determining the specificity of top2 poisons and cleavage sites for both the intercalating and non-intercalating drugs.DNA topoisomerases are enzymes that catalyze changes in the topology of DNA via a mechanism involving the transient breakage and rejoining of phosphodiester bonds in the DNA backbone (1, 2). Studies in both prokaryotic and eukaryotic cells have demonstrated the importance of topoisomerases in transcription, DNA replication, and chromosome segregation. The type II topoisomerases (top2) 1 make transient DNA double-strand breaks and change the linking number of DNA in steps of two. They play key roles in DNA metabolism and chromosome structure and are essential in eukaryotic cells (2, 3). In order to maintain the integrity of the cleaved DNA during this process, the top2 enzymes form a proteinaceous bridge that spans the DNA break. This bridge is anchored by covalent phosphotyrosyl bonds established between each of the active site tyrosine residues of the homodimeric enzyme and the 5Ј-

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Section: Different Base Preferences Of Amsacrine-and Mitoxantronestabsupporting

confidence: 93%

Section: Different Base Preferences Of Amsacrine-and Mitoxantronestabsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Analysis of Yeast and Human Type II Topoisomerases

Strumberg

Nitiss²,

Dong³

et al. 1999

Journal of Biological Chemistry

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“…The molecular details of this binding site are unknown, nevertheless, important information for its location have been revealed by mutational analysis of the cleavage of a preferred site for T4 topoisomerase which suggested that the drugs interact directly with the two bases on either side of the scissile phosphodiester bond (34). Similar conclusions were drawn by studying the local base sequence preference for DNA cleavage by mammalian topoisomerase II in the presence of anti-tumor drugs (35,36). In the case of gyrase, Cove et al (30) found that gyrase shows a preference for a pair of guanine bases being present on either side of the cleaved bond.…”

Section: Discussionmentioning

confidence: 78%

The DNA Gyrase-Quinolone Complex

Kampranis¹,

Maxwell

1998

Journal of Biological Chemistry

109

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Quinolone binding to the gyrase-DNA complex induces a conformational change that results in the blocking of supercoiling. Under these conditions gyrase is still capable of ATP hydrolysis which now proceeds through an alternative pathway involving two different conformations of the enzyme (Kampranis, S. C., and Maxwell, A. (1998) J. Biol. Chem. 269, 22606 -22614). The kinetics of ATP hydrolysis via this pathway have been studied and found to differ from those of the reaction of the drug-free enzyme. The quinolone-characteristic ATPase rate is DNA-dependent and can be induced in the presence of DNA fragments as small as 20 base pairs. By observing the conversion of the ATPase rate to the quinolone characteristic rate, the formation and dissociation of the gyrase-DNA-quinolone complex can be monitored. Comparison of the time dependence of the conversion of the gyrase ATPase with that of DNA cleavage reveals that formation of the gyrase-DNA-quinolone complex does not correspond to the formation of cleaved DNA. Quinolone-induced DNA cleavage proceeds via a mechanism consisting of two cleavage events that is modulated in the presence of a nucleotide cofactor. We demonstrate that quinolone binding and drug-induced DNA cleavage are separate processes constituting two sequential steps in the mechanism of action of quinolones on DNA gyrase.DNA gyrase is the intracellular target of the quinolone group of antibacterial agents. The addition of quinolone drugs to an in vitro reaction containing DNA gyrase, relaxed closed-circular DNA, and ATP leads to the inhibition of supercoiling (2). If this reaction is terminated by the addition of a protein denaturant, like SDS, the DNA is found to be cleaved in both strands with a gyrase A subunit (GyrA) 1 covalently attached to each 5Ј-phosphoryl terminus (3). Quinolones also inhibit the relaxation, catenation, and decatenation reactions of gyrase (2, 4).The molecular details of the interaction of the drugs with the gyrase-DNA complex are unknown. When the binding of the drugs to the enzyme was investigated, insignificant binding of quinolones to the A or B subunit (GyrB) or to the gyrase holoenzyme (A 2 B 2 ) was detected (5-7). Binding of the drugs to the DNA is weak, and more efficient in the case of singlecompared with double-stranded DNA (8,9). Quinolones were found to bind strongly to the complex formed by gyrase and DNA, and ATP appeared to assist this interaction (5). These results led to the proposal that the drugs bind to the singlestranded DNA region that is revealed when gyrase cleaves DNA during turnover (10). This proposal was addressed by site-directed mutagenesis of the gyrase active site. Mutation of tyrosine 122 to serine or phenylalanine abolished supercoiling and quinolone-induced DNA cleavage but the mutants could still bind the drugs equally well as wild-type (11). Clearly DNA cleavage is not required for drug binding. Similar results have also been obtained with topoisomerase IV (12).Using limited proteolysis we found that quinolones stabilize a conformational ...

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“…Stacking of topoisomerase poisons with the DNA base pairs immediately flanking the topoisomerase cleavage site was initially hypothesized as the mechanism of poisoning of topoisomerase II by several inhibitors of this enzyme (34)(35)(36)(37)(38). The base-stacking hypothesis has been extended to top1 poisons (camptothecins) (6,39).…”

Section: Discussionmentioning

confidence: 99%

Position-specific trapping of topoisomerase I–DNA cleavage complexes by intercalated benzo[ a ]- pyrene diol epoxide adducts at the 6-amino group of adenine

Pommier

Laco

Kohlhagen

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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DNA topoisomerase I (top1) is the target of potent anticancer agents, including camptothecins and DNA intercalators, which reversibly stabilize (trap) top1 catalytic intermediates (cleavage complexes). The aim of the present study was to define the structural relationship between the site(s) of covalently bound intercalating agents, whose solution conformations in DNA are known, and the site(s) of top1 cleavage. Two diastereomeric pairs of oligonucleotide 22-mers, derived from a sequence used to determine the crystal structure of top1-DNA complexes, were synthesized. One pair contained either a trans-opened 10R-or 10S-benzo[a]pyrene 7,8-diol 9,10-epoxide adduct at the N 6 -amino group of a central 2 -deoxyadenosine residue in the scissile strand, and the other pair contained the same two adducts in the nonscissile strand. These adducts were derived from the (؉)-(7R,8S,9S,10R)-and (؊)-(7S,8R,9R,10S)-7,8-diol 9,10-epoxides in which the benzylic 7-hydroxyl group and the epoxide oxygen are trans. On the basis of analogy with known solution conformations of duplex oligonucleotides containing these adducts, we conclude that top1 cleavage complexes are trapped when the hydrocarbon adduct is intercalated between the base pairs flanking a preexisting top1 cleavage site, or between the base pairs immediately downstream (3 relative to the scissile strand) from this site. We propose a model with the ؉1 base rotated out of the duplex, and in which the intercalated adduct prevents religation of the corresponding nucleotide at the 5 end of the cleaved DNA. These results suggest mechanisms whereby intercalating agents interfere with the normal function of human top1. D NA topoisomerase I (top1) is an essential enzyme in higher eukaryotes (1, 2). It can relax DNA supercoiling and relieve torsional strain during DNA processing, including replication, transcription, and repair. It can also perform intermolecular religation leading to DNA recombinations (3, 4). The catalytic intermediate of top1 is a cleavage complex in which a tyrosine (Tyr-723 for human top1) in the enzyme attacks a DNA phosphodiester and forms a covalent bond to the phosphorus at the 3Ј side of the cleavage site while a 5Ј-hydroxyl is generated at the other side (1, 2). The reaction occurs with short duplex oligodeoxynucleotides (5, 6), as evidenced by recent crystal structures of top1-DNA complexes (7,8).top1 is the cellular target of several anticancer drugs, including the camptothecins, which have recently been approved by the Food and Drug Administration for the treatment of colon and ovarian carcinomas. The anticancer activity of these drugs results from the trapping of top1 cleavage complexes such that the enzyme is reversibly inactivated as it cleaves DNA (9-11). These agents are often referred to as ''top1 poisons.'' They represent an exemplary case of pharmacological interference whereby the drug stabilizes the interactions of two macromolecules (i.e., top1 and DNA) by formation of a ternary complex. Because of the clinical efficacy of camptothecins, no...

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Local base sequence preferences for DNA cleavage by mammalian topoisomerase II in the presence of amsacrine or teniposide

Cited by 128 publications

References 19 publications

Molecular Analysis of Yeast and Human Type II Topoisomerases

Molecular Analysis of Yeast and Human Type II Topoisomerases

The DNA Gyrase-Quinolone Complex

Position-specific trapping of topoisomerase I–DNA cleavage complexes by intercalated benzo[ a ]- pyrene diol epoxide adducts at the 6-amino group of adenine

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