Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using specific inhibitors we have assessed the role of topoisomerases I and II in DNA repair of the overall genome and in both strands of an essential gene, the dihydrofolate reductase (DHFR) gene in chinese hamster ovary (CHO) cells. In these studies we have: (1) used inhibitors of topoisomerases during the repair incubation and (2) studied the DNA repair in cells with altered levels of topoisomerase activity. When cells were allowed to repair after UV irradiation, the gene-specific DNA repair was not affected by either topoisomerase I or topoisomerase II inhibitors alone. However, when topoisomerase I and topoisomerase II inhibitors were added simultaneously the gene- and strand-specific DNA repair were markedly inhibited. In contrast, the overall genome DNA repair was only marginally affected. This suggests that topoisomerases are involved in gene-specific DNA repair and that one type may substitute for the other in the repair process. That concept is further supported by our findings using a mutant cell line with a decreased level of topoisomerase I: gene-specific DNA repair can be inhibited by a topoisomerase II inhibitor alone. By analyzing the steady-state expression of the DHFR gene we find that inhibition of repair in the DHFR gene is not ascribed to an obvious change in the messenger level. Furthermore, using agents other than UV, we observe that the inhibitors have no effect on gene-specific repair of DNA damage introduced by the chemotherapeutic agents cisplatin and nitrogen mustard.
Carcinogenesis 1993 Sep
PMID:Studies on the role of topoisomerases in general, gene- and strand-specific DNA repair. 840 8

There is compelling evidence for the central role of oxidative damage in the aging process and for the participation of reactive oxygen species in tumor initiation and promotion. Caloric restriction (CR) or energy restriction retards age-associated increases in mitochondrial free-radical production and reduces the accumulation of oxidatively damaged cell components. CR has also been shown to slow down age-related declines in various repair capabilities, including some types of DNA repair. It is proposed that inhibitors of mitochondrial electron transport and/or uncouplers of oxidative phosphorylation (rotenone, amytal, amiodarone, valinomycin, etc.), when used at extremely low doses, could mimic the effects of CR in model systems. The objective is to lower mitochondrial free-radical production by decreasing the fraction of electron carriers in the reduced state. In addition to a variety of other effects, CR has been shown to increase the rate of apoptosis, particularly in preneoplastic cells, and in general, to promote elevated levels of free glucocorticoids (GCs). GCs are known to induce tissue-specific apoptosis and to upregulate gap-junction-mediated intercellular communication (GJIC). Tumor promoters like phorbol esters have the opposite effect, in that they inhibit both the process of apoptosis and GJIC. The enzyme poly (ADP-ribose) polymerase (PARP) is thought to play a central role in apoptosis, in a manner that has been highly conserved in evolution. There is good evidence that the apoptosis-associated Ca/Mg-dependent DNA endonuclease is maintained in a latent form by being poly (ADP-ribosylated). Apoptosis would require the removal of this polymer from the endonuclease, and, most likely, its removal from topoisomerase II and histone H1 as well. The role of poly (ADP-ribose) in apoptosis, carcinogenesis, and aging could be studied by the use of modulators of PARP activity (3-aminobenzamide, 3-nitrosobenzamide, 1% ethanol, etc.), inhibitors of poly ADP-ribose) glycohydrolase activity (ethacridine, 43 degrees C, etc.), and inhibitors of the PARP-specific protease (interleukin-1 beta converting enzyme (ICE)-like protease). Also, it would be of interest to determine if CR can decrease the half-life of poly (ADP-ribose), upregulate GJIC, and modulate the activities of PARP, the glycohydrolase, and the PARP-specific protease, factors potentially important in these processes.
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PMID:The beneficial effects of dietary restriction: reduced oxidative damage and enhanced apoptosis. 865 88

Previously, we reported that a 61-bp subgenomic HBV DNA sequence (designated as 15AB, nt 1855-1915) is a hot spot for genomic recombination and that a cellular protein binding to 15AB may be the putative recombinogenic protein. In the present study, we established the existence of a 15AB-like sequence in human and rat chromosomal DNA by Southern blot analysis. The 15AB-like sequence isolated from the rat chromosome demonstrated a 80.9% identity with 5'-CCAAGCTGTGCCTTGGGTGGC-3', at 1872-1892 of the hepatitis B virus genome, thought to be the essential region for recombination. Interestingly, this 15AB-like sequence also contained the pentanucleotide motifs GCTGG and CCAGC as an inverted repeat, part of the chi known hot spot for recombination in Escherichia coli. Importantly, a portion of the 15AB-like sequence is homologous (82.1%, 23/28 bp) to break point clusters of the human promyelocytic leukemia (PML) gene, characterized by a translocation [t(15;17)], and to rearranged mouse DNA for the immunoglobulin kappa light chain. Moreover, 15AB and 15AB-like sequences have striking homologies (12/15 = 80.0% and 13/15 = 86.7%, respectively) to the consensus sequence for topoisomerase II. Our present results suggest that this 15AB-like sequence in the rat genome might be a recombinogenic candidate triggering genomic instability in carcinogenesis.
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PMID:Molecular cloning of a rat chromosome putative recombinogenic sequence homologous to the hepatitis B virus encapsidation signal. 869 87

This paper describes molecular and cytogenetic evidence for the stability of a transgene locus that is present on the triplicated chromosome in an aneuploid tobacco line. This instability was manifested in several ways in trisomics including a major chromosome rearrangement that was detectable cytogenetically, smaller scale DNA rearrangements that occurred both germinally and somatically, and methylation/epigenetic silencing. In a deletion derivative of the locus, DNA breakpoints were found in AT-rich regions. One of these regions binds to nuclear scaffolds in vitro, suggesting a possible role for aberrant topoisomerase II cleavage in destabilization of the locus. The implications of increased chromosome instability in aneuploids for plant karyotype evolution and human carcinogenesis are discussed.
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PMID:Structural instability of a transgene locus in tobacco is associated with aneuploidy. 881 61

Soy-based diets, rich in the isoflavones genistein and daidzein, are thought to protect against breast and prostate cancer. We used the N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis animal model to test the effectiveness of these two isoflavones as chemopreventive agents. Each isoflavone was injected daily into 35-day-old rats for six months while we monitored the animals' body weight and mammary tumor appearance. Genistein was effective in reducing tumor multiplicity, but it reduced tumor incidence only marginally. Daidzein was less effective in reducing both tumor incidence and multiplicity. To investigate genistein's mechanism of action, we determined the topoisomerase II (topo II) activity and detected the phosphotyrosine-containing peptides in the extracts of mammary tissues isolated from control and isoflavone-treated animals. Mammary tumors contained over 60-fold higher topo II enzymatic activity than the mammary glands. Similarly, more tyrosine phosphopeptides were detectable in mammary tumors than in mammary glands. Tissue samples from genistein treated animals contained similar topo II and protein tyrosine kinase (PTK) activities as the control group. These data suggest that mammary tumorigenesis is accompanied by an extensive increase in topo II and PTK activities. The mechanism of chemoprevention by genistein, however, is independent of topo II or PTK inhibition.
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PMID:Inhibition of N-methyl-N-nitrosourea-induced mammary tumors in rats by the soybean isoflavones. 904 3

This paper examines the relationship between DNA mutagenic lesions, DNA methylation and the involvement of these changes in the process of carcinogenesis. Many types of DNA damage (oxidative lesions, alkylation of bases, abasic sites, photodimers, etc.) interfere with the ability of mammalian cell DNA to be methylated at CpG dinucleotides by DNA-methyltransferases (DNA-MTases). This can result in altered patterns in the distribution of 5-methylcytosine (5MeC) residues at CpG sites. Methylation of DNA is an epigenetic change that by definition is heritable, can result in changes in chromatin structure, and is often accompanied by modified patterns of gene expression. The presence of 5MeC in DNA, as well as oxidative stress induced by the free radical nitric oxide, can interefere with the repair of alkylation damage, thereby increasing the level of potentially mutagenic lesions. CpG sites in DNA represent mutational hotspots, with both the presence of 5MeC in DNA and the catalytic activity of DNA-MTases being intrinsically mutagenic. The process of carcinogenesis has frequently been associated with an increased expression of DNA-MTase activity, accompanied by either hypermethylation or hypomethylation of target cell (progenitor tumor cell) DNA. In addition, there is evidence that overexpression of DNA-MTase activity could result in increased cytosine methylation at non-CpG sites. A variety of chemicals can alter the extent of DNA methylation in mammalian cells. These include inhibitors of topoisomerase II, as well as inhibitors of DNA synthesis, microtubule formation, histone deacetylation, transmethylation, etc. Genetic and epigenetic changes in DNA have a profound influence on one another and could play a major role in the process of carcinogenesis, by modulating both the extent and the pattern of gene expression.
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PMID:DNA methylation and the association between genetic and epigenetic changes: relation to carcinogenesis. 912 74

Etoposides block cell division by interfering with the action of topoisomerase II, leaving enzyme-DNA double-strand breaks. We found that certain components of the trimeric DNA-dependent protein kinase influence cell survival following etoposide damage. Interestingly, either Ku70- or Ku80-deficient cell lines, but not mutant cell lines of the DNA-PK catalytic sub-unit (DNA-PKcs), were found to be hypersensitive to the effects of etoposide VP16. Ku70- and Ku80-deficient cells can be complemented to an etoposide resistant phenotype by introducing wildtype Ku70 or Ku80 cDNAs. Mutational analysis of introduced Ku70 cDNAs into murine embryonic stem cells deleted for Ku70 (-/-) showed that mutants where heterodimerization and DNA binding functions of Ku were disrupted, also blocked the restoration of etoposide resistance. In contrast with the differential etoposide sensitivity of DNA-PK mutants, both Ku- and DNA-PKcs-deficient cell lines showed G2 ionizing radiation-induced delays, a cell cycle phase where topoisomerase II function is critical. Thus, the topoisomerase II cleaved complexes may be an example of DNA lesions requiring the Ku heterodimer, but not DNA-PK for DNA repair.
Carcinogenesis 1998 Jun
PMID:Differential etoposide sensitivity of cells deficient in the Ku and DNA-PKcs components of the DNA-dependent protein kinase. 966 32

Many inhibitors of topoisomerase II enzymes are potent mutagens, leading to major chromosomal deletions, illegitimate recombination and aneuploidy. There is increasing evidence that they are also human carcinogens. However, their lack of chemical reactivity means that they may give weak or negative results in commonly used mutagenicity tests, or may give data with characteristics quite distinct from chemicals that alkylate DNA. They do not form DNA adducts and assays such as 32P-postlabelling will not detect their presence in the body. They are generally not point mutagens and may fail to provide distinctive fingerprints in mutation spectra. These characteristics may be limiting a realistic evaluation of their role in human carcinogenesis using current methodologies.
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PMID:Inhibitors of topoisomerase II enzymes: a unique group of environmental mutagens and carcinogens. 968 77

Somatic changes in CpG dinucleotide methylation occur quite commonly in human cancer cell DNA. Relative to DNA from normal human colonic cells, DNA from human colorectal cancer cells typically displays regional CpG dinucleotide hypermethylation amid global CpG dinucleotide hypomethylation. The role of the maintenance DNA methyltransferase (DNMT1) in the acquisition of such abnormal CpG dinucleotide methylation changes in colorectal cancer cells remains controversial; in one study, 60-200-fold increases in DNMT1 mRNA expression were detected in colorectal polyps and cancers relative to normal colonic tissue [W. S. El-Deiry et al., Proc. Natl. Acad. Sci. USA, 88: 3470-3474, 1991], whereas in another study, only small increases in DNMT1 mRNA expression, commensurate with differences in cell proliferation accompanying colonic tumorigenesis, were observed [P. J. Lee et al., Proc. Natl. Acad. Sci. USA, 93: 10366-10370, 1996]. To definitively ascertain whether abnormal DNMT1 expression might accompany human colorectal carcinogenesis, we subjected a series of normal and neoplastic colonic tissues to immunohistochemical staining using a polyclonal antiserum raised against a DNMT1 polypeptide. A concordance of DNMT1 expression with the expression of PCNA and other cell proliferation markers, such as Ki-67 and DNA topoisomerase IIalpha, was observed in normal colonic epithelial cells and in cells comprising other normal epithelia and lymphoid tissues. The polypeptide p21, which has been reported to undermine DNMT1 binding to proliferating cell nuclear antigen at DNA replication sites, was not expressed by normal colonic cells containing DNMT1 and other cell proliferation markers. In adenomatous polyps, although DNMT1 expression coincided with the expression of other cell proliferation markers, many DNMT1-expressing cells also expressed p21. The fidelity of DNMT1 expression was further undermined in colorectal carcinomas, in which a striking heterogeneity in DNMT1 expression, with some carcinoma cells containing very high DNMT1 levels and others containing very low DNMT1 levels, was observed. These results indicate that human colorectal carcinogenesis is accompanied by a progressive dysregulation of DNMT1 expression and suggest that abnormalities in DNMT1 expression may contribute to the abnormal CpG dinucleotide methylation changes characteristic of human colorectal carcinoma cell DNA.
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PMID:Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis. 1046 69

We review the history of the toxicology of benzene and consider current exposure levels, the metabolism of benzene, reactions of the metabolites with biomolecules and possible mechanisms of carcinogenesis due to benzene. Epidemiological evidence indicates a relationship between exposure to benzene and the occurrence of acute non-lymphocytic leukaemia in humans. Working groups convened by IARC and other organizations have therefore judged that there is sufficient evidence for classifying benzene as a human carcinogen. Despite much research, including numerous studies in animals, the detailed mechanism of the carcinogenicity of benzene is unknown. The significant differences in the responses of rodents and humans to benzene are not understood. Benzene forms many metabolites, some of which are reactive towards biomolecules, but the metabolite(s) responsible for the induction of leukaemia is unknown. Candidate metabolites, either singly or in combination, include epoxides, oxepins, quinones and aldehydes, all of which are reactive towards proteins and DNA. Our studies on muconaldehydes and benzene oxide-oxepin are discussed in this context. The significance of DNA adduct formation in respect of human leukaemia is uncertain. The overall reactivity of benzene towards DNA has been shown to be very low in experimental animals, although dose-related reactivity of metabolites with DNA was observed. The lack of significant DNA reactivity is reflected in the lack of activity of benzene in short-term tests for genotoxicity; however, benzene causes oxidative stress, which can be detected as oxidative damage to DNA. Mechanisms other than DNA damage may play a role in benzene-related toxicity, e.g. reactions of benzene metabolites with essential enzymes such as topoisomerase II.
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PMID:Possible mechanisms of carcinogenesis after exposure to benzene. 1062 10


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