DNA Topoisomerase II as the Target for the Anticancer Drug TOP-53:  Mechanistic Basis for Drug Action

Byl, Jo Ann W.; Cline, Susan D.; Utsugi, Teruhiro; Kobunai, Takashi; Yamada, Yuji; Osheroff, Neil

doi:10.1021/bi0021838

Cited by 77 publications

(54 citation statements)

References 44 publications

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“…For example, camptothecins have been shown to be highly specific for topoisomerase I (12,24). Similarly, epipodophyllotoxins and other topoisomerase II-targeting agents have also been shown to be highly specific for their targets (5,17,29). Since both topoisomerase I and topoisomerase II are targets for active anticancer agents, understanding cellular responses to these agents also lends insight into their appropriate clinical use.…”

Section: Discussionmentioning

confidence: 99%

“…Unknown Unknown It is very likely that TOP-53 acts specifically on topoisomerase II, since it has been shown to specifically target topoisomerase II in S. cerevisiae (5,31). Sensitivity to doxorubicin and mitoxantrone was also seen; however, these agents have mechanisms of cell killing that are independent of the presence of topoisomerase II (27).…”

Section: Spmentioning

confidence: 99%

“…TOP-53 specifically targets topoisomerase II and is not active against other possible cytotoxic targets (5). One important function that we examined in this work is the role of genes required for recombinational repair in cell survival following treatment with topoisomerase-targeting agents.…”

Section: Vol 3 2004 Topoisomerase-mediated Damage In S Pombe 87mentioning

confidence: 99%

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DNA Repair Functions That Control Sensitivity to Topoisomerase-Targeting Drugs

Malik

Nitiss

2004

Eukaryot Cell

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DNA topoisomerases play critical roles in a wide range of cellular processes by altering DNA topology to facilitate replication, transcription, and chromosome segregation. Topoisomerases alter DNA topology by introducing transient DNA strand breaks that involve a covalent protein DNA intermediate. Many agents have been found to prevent the religation of DNA strand breaks induced by the enzymes, thereby converting the enzymes into DNA-damaging agents. Repair of the DNA damage induced by topoisomerases is significant in understanding drug resistance arising following treatment with topoisomerase-targeting drugs. We have used the fission yeast Schizosaccharomyces pombe to identify DNA repair pathways that are important for cell survival following drug treatment. S. pombe strains carrying mutations in genes required for homologous recombination such as rad22A or rad32 (homologues of RAD52 and MRE11) are hypersensitive to drugs targeting either topoisomerase I or topoisomerase II. In contrast to results observed with Saccharomyces cerevisiae, S. pombe strains defective in nucleotide excision repair are also hypersensitive to topoisomerase-targeting agents. The loss of DNA replication or DNA damage checkpoints also sensitizes cells to both topoisomerase I and topoisomerase II inhibitors. Finally, repair genes (such as the S. pombe rad8 ؉ gene) with no obvious homologs in other systems also play important roles in causing sensitivity to topoisomerase drugs. Since the pattern of sensitivity is distinct from that seen with other systems (such as the S. cerevisiae system), our results highlight the usefulness of S. pombe in understanding how cells deal with the unique DNA damage induced by topoisomerases.Topoisomerases are cellular enzymes that modify the topological state of DNA and participate in metabolic processes such as replication, recombination, transcription, and chromosome segregation (26, 44). These enzymes work by breaking the DNA backbone, carrying out strand passage through the broken DNA, and resealing the break. DNA cleavage by topoisomerases occurs by the introduction of DNA single-or double-strand breaks by a transesterification reaction, in which a tyrosine residue forms a catalytic intermediate that includes a covalent bond between the enzyme and DNA (44).In addition to their critical biological functions, topoisomerases are the targets of a wide range of antibacterial and antitumor agents. For example, eukaryotic topoisomerase I is the target of camptothecin analogs and agents such as fluoroquinolones and anthracyclines target topoisomerase II (8,11,19,28). These antibacterial and antitumor drugs interfere with the catalytic cycle of topoisomerases by elevating the levels of the covalent complex formed between the enzymes and the cleaved DNA. Agents such as etoposide and amsacrine elevate the levels of covalent complexes by inhibiting the topoisomerase-mediated religation of the cleaved DNA (37). The enzyme:DNA covalent complex, although reversible, can be converted into irreversible DNA damage by var...

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Section: Discussionmentioning

confidence: 99%

Section: Spmentioning

confidence: 99%

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DNA Repair Functions That Control Sensitivity to Topoisomerase-Targeting Drugs

Malik

Nitiss

2004

Eukaryot Cell

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“…In contrast to etoposide and teniposide, TOP-53 contains a flexible dicationic amino-alkyl chain at the C4 position (see Figure 1) (51). Although TOP-53 is structurally identical to these compounds at all other positions, it exhibits a significantly greater ability (~4-fold higher potency) to stimulate DNA cleavage mediated by yeast (see Figure 2) or human type II topoisomerases (52). This finding implies that substituents at the C4 position have the capacity to alter drug actions in the ternary complex.…”

Section: C4 Substituentsmentioning

confidence: 98%

Topoisomerase II−Drug Interaction Domains: Identification of Substituents on Etoposide That Interact with the Enzyme

et al. 2007

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Etoposide is one of the most successful chemotherapeutic agents used for the treatment of human cancers. The drug kills cells by inhibiting the ability of topoisomerase II to ligate nucleic acids that it cleaves during the double-stranded DNA passage reaction. Etoposide is composed of a polycyclic ring system (rings A-D), a glycosidic moiety at the C4 position, and a pendant ring (E-ring) at the C1 position. Although drug-enzyme contacts, as opposed to drug-DNA interactions, mediate the entry of etoposide into the topoisomerase II-drug-DNA complex, the substituents on etoposide that interact with the enzyme have not been identified. Therefore, saturation transfer difference [ 1 H]-nuclear magnetic resonance spectroscopy and protein-drug competition binding assays were employed to define the groups on etoposide that associate with yeast topoisomerase II and human topoisomerase IIα. Results indicate that the geminal protons of the A-ring, the H5 and H8 protons of the B-ring, as well as the H2' and H6' protons and the 3'-and 5'-methoxyl protons of the pendent E-ring interact with both enzymes in the binary protein-ligand complexes. In contrast, no significant nuclear Overhauser enhancement signals arising from the C-ring, the D-ring, or the C4 glycosidic moiety were observed with either enzyme, suggesting that there is limited or no contact between these portions of etoposide and topoisomerase II in the binary complex. The functional importance of E-ring substituents was confirmed by topoisomerase II-mediated DNA cleavage assays.Etoposide is one of the most successful chemotherapeutic agents used for the treatment of human cancers (1-4). The drug currently is in its third decade of clinical use and is front line

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“…This mechanism of DNA breakage can create difficulties for a cell under conditions that interfere with the normal religation reaction of the enzyme, such as the presence of specific inhibitors. Then, the enzyme becomes trapped on DNA as a stable covalent adduct (2). Topos can become trapped by small molecule inhibitors such as camptothecin or etoposide, which are clinically used anticancer agents targeting topo I and topo II, respectively.…”

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confidence: 99%

Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage

Nitiss¹,

Malik²,

et al. 2006

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

146

119

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Agents targeting topoisomerases are active against a wide range of human tumors. Stabilization of covalent complexes, converting topoisomerases into DNA-damaging agents, is an essential aspect of cell killing by these drugs. A unique aspect of the repair of topoisomerase-mediated DNA damage is the requirement for pathways that can remove protein covalently bound to DNA. Tyrosyl-DNA phosphodiesterase (Tdp1) is an enzyme that removes phosphotyrosyl moieties bound to the 3 end of DNA. Cells lacking Tdp1 are hypersensitive to camptothecin, consistent with a role for Tdp1 in processing 3 phosphotyrosyl protein-DNA covalent complexes. Because Top2p forms a 5 phosphotyrosyl linkage with DNA, previous work predicted that Tdp1p would not be active against lesions involving Top2p. We found that deletion of the TDP1 gene in yeast confers hypersensitivity to Top2 targeting agents. Combining tdp1 mutations with deletions of genes involved in nonhomologous end joining, excision repair, or postreplication repair enhanced sensitivity to Top2 targeting drugs over the level seen with single mutants, suggesting that Tdp1 may function in collaboration with multiple pathways involved in strand break repair. tdp1 mutations can sensitize yeast cells to drugs targeting Top2 even when TOP1 is deleted. Finally, bacterially expressed yeast Tdp1p is able to remove a peptide derived from yTop2 that is covalently bound to DNA by a 5 phosphotyrosyl linkage. Our results show that Tdp1 plays more general roles in DNA repair than repair of Top1 mediated DNA damage, and may participate in repairing many types of base damage to DNA.D NA topoisomerases (topos) carry out alterations in DNA structure by transiently introducing breaks in DNA. Topos use tyrosine residues to form a transient covalent intermediate between the enzyme and DNA, resulting in single or double strand DNA breaks (1). This mechanism of DNA breakage can create difficulties for a cell under conditions that interfere with the normal religation reaction of the enzyme, such as the presence of specific inhibitors. Then, the enzyme becomes trapped on DNA as a stable covalent adduct (2). Topos can become trapped by small molecule inhibitors such as camptothecin or etoposide, which are clinically used anticancer agents targeting topo I and topo II, respectively. The complete repair of this type of lesion requires DNA strand break repair pathways, and also requires activities that can remove covalent protein DNA adducts (3).An enzyme described by Nash and colleagues (4), tyrosyl-DNA phosphodiesterase (Tdp1), can remove peptides covalently bound to DNA by a 3Ј phosphotyrosine linkage. This enzyme participates in the repair of Top1 covalently trapped on DNA in the presence of camptothecin in both yeast (5, 6) and mammalian cells (7). Tdp1 is a phospholipase D superfamily enzyme (8), and the three-dimensional structure of the protein (9) as well as transition state intermediates have been reported (10). Tdp1 does not define the only pathway for removing Top1 that is trapped by camptothecin, ...

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DNA Topoisomerase II as the Target for the Anticancer Drug TOP-53: Mechanistic Basis for Drug Action

Cited by 77 publications

References 44 publications

DNA Repair Functions That Control Sensitivity to Topoisomerase-Targeting Drugs

DNA Repair Functions That Control Sensitivity to Topoisomerase-Targeting Drugs

Topoisomerase II−Drug Interaction Domains: Identification of Substituents on Etoposide That Interact with the Enzyme

Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage

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