Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme

Pommier, ﻿Yves; Pourquier, Philippe; Fan, Yi; Strumberg, Dirk

doi:10.1016/s0167-4781(98)00129-8

Cited by 523 publications

(489 citation statements)

References 230 publications

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“…These drugs however, when administered to patients, may kill normal cells and thus result in debilitating side effects (Keyomarsi & Pardee, 2003; Most anti-tumoral agents are designed to action cell proliferation (Green et al, 2011) and apoptosis induction (Peng et al, 2003). Drugs inhibit DNA synthesis by two mechanisms that are generally associated: the drug either binds to DNA by intercalation and stops the replication ; or interferes directly with molecules required for DNA polymerization and/or initiation of replication (Pommier et al, 1998;Bruning & Mylonas et al, 2011). The ability of such drugs to intercalate into DNA can induce mutations in normal cells (Hoffmann et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

Assessment of estrogenic, mutagenic and antimutagenic activity of nemorosone

Camargo¹,

Varela²,

Oliveira³

et al. 2011

Rev. bras. farmacogn.

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Currently, a wide range of research involving natural products is focused on the discovery of new drugs in many different therapeutic areas. A great number of the synthetic compounds on the market were derived from natural products, especially plants. Nemorosone is the major constituent of the floral resin of Clusia rosea Jacq., Clusiaceae, and in Cuban propolis. In vitro studies have shown cytotoxic activity in this substance against various tumor cell lines, including those resistant to various cytotoxic drugs, whereas it has low cytotoxicity to non-tumoral cells. Therefore, in order to characterize the biological activity of nemorosone, a substance with potential antitumor activity, and in view of preclinical testing of the toxicity of drug candidate compounds, the main aim of this study was to determine the mutagenic and antimutagenic activity of nemorosone by the Ames test, using the strains TA97a, TA98, TA100 and TA102 of Salmonella typhimurium. Secondly, to characterize the estrogenic activity in an experimental recombinant yeast model (Recombinant Yeast Assay) mutagenic activity was observed at in any of the concentrations in any of the test strains. To evaluate the antimutagenic potential, direct and indirect mutagenic agents were used: 4 nitro-o-phenylenediamine (NPD), mitomycin C (MMC) and aflatoxin B1 (AFL). Nemorosone showed moderate antimutagenic activity (inhibition level 31%), in strain TA100 in the presence of AFL, and strong antimutagenic activity in TA102 against MMC (inhibition level 53%). Estrogenic activity was observed, with an EEq of 0.41±0.16 nM at various tested concentrations.

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Section: Resultsmentioning

confidence: 99%

Assessment of estrogenic, mutagenic and antimutagenic activity of nemorosone

Camargo¹,

Varela²,

Oliveira³

et al. 2011

Rev. bras. farmacogn.

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“…We found viable mph1 srs2 segregants synergistically sensitive to MMS and 4-NQO, thought to form DNA lesions potently blocking replisome progression (Pegg, 1984;Ramotar et al, 1998) and, in particular, sensitive to camptothecin ( Figure 4A). Camptothecin is thought to induce replication fork collapse and the formation of double-strand ends (Pommier et al, 1998;Strumberg et al, 2000;Lin et al, 2000). The only way to restart replication in this case is probably via HR.…”

Section: Discussionmentioning

confidence: 99%

“…2. mph1 and srs2 single mutants show moderate sensitivity to camptothecin (Scheller et al, 2000;Mankouri et al, 2002), which is synergistically increased in viable mph1 srs2 mutants ( Figure 4A). This could indicate fork collapse, as induced by camptothecin (Pommier et al, 1998;Strumberg et al, 2000;Lin et al, 2000), to seriously compromise viability of mph1 srs2 cells. The models in Figure 6 could account for this observations.…”

Section: Mph1 Is Likely To Have a Role In Recombinational Dna Repair mentioning

confidence: 99%

Genetic evidence for a role of Saccharomyces cerevisiae Mph1 in recombinational DNA repair under replicative stress

Panico

Ede

Schildmann

et al. 2009

Yeast

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In yeast as in human, DNA helicases play critical roles in assisting replication fork progression. The Saccharomyces cerevisiae MPH1 gene, homologue of human FANCM, has been involved in homologous recombination and DNA repair. We describe a synthetic growth defect of an mph1 deletion if combined with an srs2 deletion that can result -depending on the genetic background -in synthetic lethality. The lethality is suppressed by mutations in homologous recombination (rad51, rad52, rad55, rad57 ) and in the DNA damage checkpoint (rad9, rad24, rad17 ). Importantly, rad54 and mph1, epistatic for damage sensitivity, are subadditive for spontaneous mutator phenotype. Therefore, Mph1 could be placed at the Rad51-mediated strand invasion process, with a function distinct from Rad54. Moreover, siz1 mutation is viable with mph1 and additive for DNA damage sensitivity. mph1 srs2 double mutants, isolated in a background where they are viable, are synergistically sensitive to DNA damage. Moderate overexpression of SGS1 partially suppresses this sensitivity. Finally, we observe an epistatic relationship in terms of sensitivity to camptothecin of mms4 or mus81 to mph1. Overall, our results support a role of Mph1 in assisting replication progression. We propose two models for the resumption of DNA synthesis under replicative stress where Mph1 is placed at the sister chromatid interaction step.

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“…Type I topoisomerases act by generating a transient single-stranded break in the double helix, followed by either a single-stranded DNA passage event or controlled rotation about the break [5,12,14,18,21,22]. As a result, these enzymes are able to alleviate torsional stress (i.e., remove superhelical twists) in duplex DNA.…”

Section: Dna Topoisomerasesmentioning

confidence: 99%

“…As a result, these enzymes are able to alleviate torsional stress (i.e., remove superhelical twists) in duplex DNA. Type I topoisomerases are involved in all DNA processes that involve tracking systems and play important roles in maintaining genomic integrity [5,7,13,14,18,21,22].…”

Section: Dna Topoisomerasesmentioning

confidence: 99%

DNA topoisomerase II, genotoxicity, and cancer

McClendon

Osheroff

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

363

466

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Type II topoisomerases are ubiquitous enzymes that play essential roles in a number of fundamental DNA processes. They regulate DNA under-and overwinding, and resolve knots and tangles in the genetic material by passing an intact double helix through a transient double-stranded break that they generate in a separate segment of DNA. Because type II topoisomerases generate DNA strand breaks as a requisite intermediate in their catalytic cycle, they have the potential to fragment the genome every time they function. Thus, while these enzymes are essential to the survival of proliferating cells, they also have significant genotoxic effects. This latter aspect of type II topoisomerase has been exploited for the development of several classes of anticancer drugs that are widely employed for the clinical treatment of human malignancies. However, considerable evidence indicates that these enzymes also trigger specific leukemic chromosomal translocations. In light of the impact, both positive and negative, of type II topoisomerases on human cells, it is important to understand how these enzymes function and how their actions can destablize the genome. This article discusses both aspects of human type II topoisomerases.

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Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme

Cited by 523 publications

References 230 publications

Assessment of estrogenic, mutagenic and antimutagenic activity of nemorosone

Assessment of estrogenic, mutagenic and antimutagenic activity of nemorosone

Genetic evidence for a role of Saccharomyces cerevisiae Mph1 in recombinational DNA repair under replicative stress

DNA topoisomerase II, genotoxicity, and cancer

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