Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A protein required for the elongation of replicating intermediates of adenovirus (Ad) DNA to full length has been isolated and characterized. This factor, isolated from nuclear extracts of uninfected HeLa cells, has been designated nuclear factor II. In the presence of Ad DNA with proteins at each 5' end (Ad DNA-protein) and three proteins coded for by the Ad genome [the preterminal protein (pTP), the DNA polymerase (Ad Pol), and the DNA binding protein (Ad DBP)], nuclear factor II complementing activity is detected only in the presence of host nuclear factor I. Highly purified preparations of nuclear factor II that are free of detectable DNA polymerase alpha, beta, and gamma activities contain a DNA topoisomerase activity. Furthermore, type I DNA topoisomerases purified from HeLa cells and calf thymus substitute for nuclear factor II complementing activity in the in vitro Ad DNA replication system. These results indicate that a protein that is involved in higher order DNA structure is required for Ad replication. This protein plus the purified proteins described above carry out the initiation and synthesis of full-length 36,000-base-pair Ad DNA.
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PMID:Adenovirus DNA replication in vitro: synthesis of full-length DNA with purified proteins. 630 11

We have investigated the loop organization of a 835 kilobases DNA fragment from the Drosophila genome. This analysis has focused on the periodicity of the distribution of anchoring sequences (SARs) and its relationship to the distribution of A,T-rich regions, transcription units, repeated elements, putative replication origins and topoisomerase II cleavage sites. Altogether, the data support the idea of an active participation of SARs to the structural organization and functioning of this eukaryotic genome.
Acta Biochim Pol 1995
PMID:SARs on an 835 kb DNA fragment from the Drosophila genome. 858 58

The treatment of agarose embedded plant nuclei by strong protein denaturants was demonstrated to result in discrete self-fragmentation of intact nuclear DNA. The set of resultant DNA cleavage products involves two main types of DNA fragments sized about 50-100 kb and 300-500 kb, being of the same type in various eukaryotic representatives. The pattern of ordered DNA fragmentation has been shown to be similar both in intact nuclei and in histone-depleted ones thus suggesting that the observed DNA fragments represent preexisting DNA structural domains, corresponding to the higher levels of chromatin folding. The topoisomerase II-specific poison teniposide (VM-26) has been shown to increase the ordered DNA cleavage while the conditions stimulating the topoisomerase II-mediated reverse reaction lead to the reassociation of the cleaved DNA domains. The data presented suggest that the nuclear DNA structural domains are involved in functioning of the topoisomerase II/DNA complex, the main property of which is its ability to mediate the cleavage/reassociation reactions.
Acta Biochim Pol 1995
PMID:Structural domains of plant nuclear DNA as a constitutive component of the topoisomerase II/DNA complex. 858 64

Type II DNA topoisomerases are required for the segregation of genomic DNA at cell division in prokaryotic and eukaryotic cells, and inhibitors of these enzymes are potential cytotoxic agents in both prokaryotes and eukaryotes. The bacterial member of the topoisomerase II family, DNA gyrase, and the chemotherapeutic agents which target it are the subject of a recent review (Maxwell, A. et al., 1993, in Molecular Biology of DNA Topoisomerases, Andoh, T. et al., eds., pp. 21-30, CRC Press, Boca Raton). Here we present an overview of current knowledge of eukaryotic topoisomerase II and the anticancer agents which target this enzyme, focussing predominantly on new observations and recent reports and reviews.
Acta Biochim Pol 1995
PMID:Topoisomerase II as a target for anticancer chemotherapy. 885 29

The identity of DNA replication proteins and cell cycle regulatory proteins which can be found in complexes involving PCNA were investigated by the use of PCNA immobilized on Sepharose 4B. A column containing bovine serum albumin (BSA) bound to Sepharose was used as a control. Fetal calf thymus extracts were chromatographed on PCNA-Sepharose and BSA-Sepharose. The columns were washed and then eluted with 0.5 M KCl. The salt eluates were examined for the presence of both DNA replication proteins (Pol alpha, delta, straightepsilon, PCNA, RFC, RFA, DNA ligase I, NDH II, Topo I and Topo II) and cell cycle proteins (Cyclins A, B1, D1, D2, D3, E, CDK2, CDK4, CDK5 and p21) by western blotting with specific antibodies. The DNA replication proteins which bound to PCNA-Sepharose included DNA polymerase delta and straightepsilon, PCNA, the 37 and 40 kDa subunits of RFC, the 70 kDa subunit of RPA, NDH II and topoisomerase I. No evidence for the binding of DNA polymerase alpha, DNA ligase I or topoisomerase II was obtained. Of the cell cycle proteins investigated, CDK2, CDK4 and CDK5 were bound. This study presents strong evidence that PCNA is a component of protein complexes containing DNA replication, repair and cell cycle regulatory proteins.
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PMID:Identification of DNA replication and cell cycle proteins that interact with PCNA. 939 13

A number of large extrachromosomal elements encode prokaryotic type I topoisomerases of unknown functions. Here, we analysed the topoisomerase Topbeta encoded by the Gram-positive broad-host-range plasmid pAMbeta1. We show that this enzyme possesses the DNA relaxation activity of type I topoisomerases. Interestingly, it is active only on plasmids that use DNA polymerase I to initiate replication, such as pAMbeta1, and depends on the activity of this polymerase. This is the first example, to our knowledge, of prokaryotic type I topoisomerase that is specific for a given type of replicon. During pAMbeta1 replication in Bacillus subtilis cells, Topbeta promotes premature arrest of DNA polymerase I, approximately 190bp downstream of the replication initiation point. We propose that Topbeta acts on the early replication intermediates of pAMbeta1, which contain D-loops formed by DNA polymerase I-mediated strand displacement. The possible role of the resulting DNA Pol I arrest in plasmid replication is discussed.
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PMID:In vivo relations between pAMbeta1-encoded type I topoisomerase and plasmid replication. 966 86

DNA topoisomerases regulate the organization of DNA and are important targets for many clinically used antineoplastic agents. In addition, DNA topoisomerases modulate the cellular sensitivity toward a number of DNA damaging agents. Increased topoisomerase II activities were shown to contribute to the resistance of both nitrogen mustard- and cisplatin-resistant cells. Similarly, cells with decreased topoisomerase II levels show increased sensitivity to cisplatin, carmustine, mitomycin C and nitrogen mustard. Recent studies propose that topoisomerases may be involved in damage recognition and DNA repair at several different levels including: 1) the initial recognition of DNA lesions; 2) DNA recombination; and 3) regulation of DNA structure. The stress-activated oncogene suppressor protein p53 can modulate the activity of at least three different human topoisomerases, either directly by molecular associations or by transcriptional regulation. Since DNA topoisomerases have considerable recombinase activities, inappropriately activated topoisomerases in tumor cells lacking functional p53 may contribute to the genetic instability of these cells.
Acta Biochim Pol 1998
PMID:DNA topoisomerases as repair enzymes: mechanism(s) of action and regulation by p53. 982 82

Genistein--a soy derived isoflavone has recently attracted much attention of the medical scientific community. This compound was found to be a potent agent in both prophylaxis and treatment of cancer as well as other chronic diseases. The great interest that has focused on genistein led to the identification of numerous intracellular targets of its action in the live cell. At the molecular level, genistein inhibits the activity of ATP utilizing enzymes such as: tyrosine-specific protein kinases, topoisomerase II and enzymes involved in phosphatidylinositol turnover. Moreover, genistein can act via an estrogen receptor-mediated mechanism. At the level one step higher, i.e., at the cellular level, genistein induces apoptosis and differentiation in cancer cells, inhibits cell proliferation, modulates cell cycling, exerts antioxidant effects, inhibits angiogenesis, and suppresses osteoclast and lymphocyte functions. These activities make genistein a promising innovative agent in the treatment of cancer. Additionally, genistein health beneficial effects have been shown in osteoporosis, cardiovascular diseases and menopause. Genistein was also successfully used as an immunosuppressive agent both in vitro and in vivo. All these effects at the three biological levels of action need varied genistein concentrations and only some of them are relevant in people consuming soy-rich diet. The others would occur after purified genistein administration at higher doses. The main genistein advantage as a potential drug is its multidirectional action in the live cell and its very low toxicity.
Acta Pol Pharm
PMID:Biological properties of genistein. A review of in vitro and in vivo data. 1093 94

Genistein, a principal soy isoflavone, has recently aroused interest in medical research owning to its numerous biochemical properties such as: inhibition of the activity of tyrosine-specific protein kinases and topoisomerase II, estrogenic and antioxidant activity as well as antiproliferative and antiangiogenic effects. Therefore, genistein is extensively investigated as a novel anticancer drug. To improve physicochemical properties of genistein (e.g., water solubility) we have synthesized its complexes with amines. Genistein-piperazine complex (GP) has been then examined whether it exhibits anticancer action against human promyelocytic leukemia cell line (HL-60) cultured in vitro. The parallel study with pure genistein has also been undertaken. Cell proliferation, viability, apoptosis and cell cycle kinetics have been assayed for various drugs concentrations (10-40 microM) and periods of exposure (1-6 days). GP reduced proliferation rate, decreased cell viability and induced apoptotic cell death, in a dose- and time-dependent manner. Flow-cytometric analysis of cell cycle distribution revealed a progressive and sustained accumulation of cells in the G2/M phase that was accompanied by unperturbed protein synthesis. The measured anticancer effects of GP and genistein were qualitatively and quantitatively similar, indicating that genistein-amine complex does not loose the activity of the parent compound.
Acta Pol Pharm
PMID:Anticancer activity of genistein-piperazine complex. In vitro study with HL-60 cells. 1114 12

A series of proline analogues of anthraquinone-2-carboxylic acid (1-3) were synthesized and evaluated for cytotoxic activity in the cultured breast cancer MCF-7 cells. The concentrations of 1, 2 and 3 needed to inhibit [3H]thymidine incorporation into DNA by 50% (IC50) were found to be 107 +/- 6 microM, 185 +/- 5 microM and 87 +/- 6 microM, respectively. To test whether cytotoxic properties were related to topoisomerase action, the most potent compounds 1 and 3 were evaluated in a cell-free system. Compound 3, which contains a basic substituent at C terminus of the amino acid such as (dimethylamino)propyl inhibited the catalytic activity of both topoisomerases I and II at a concentration of 30 and 60 microM, respectively. However, compound 1 containing an electrostatically neutral moiety, such as methyl ester did not inhibit topoisomerase I or topoisomerase II. In summary, compound 3 is a promising lead compound for a further structural variation in the design of new antitumour drugs.
Pol J Pharmacol
PMID:L-proline analogues of anthraquinone-2-carboxylic acid: cytotoxic activity in breast cancer MCF-7 cells and inhibitory activity against topoisomerase I and II. 1178 29


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