Disease relevance of Top1

• OBJECTIVE: Autoantibodies to DNA topoisomerase I (topo I) are associated with diffuse systemic sclerosis (SSc), appear to be antigen driven, and may be triggered by cryptic epitopes exposed during in vivo topo I fragmentation [1].
• DNA topoisomerase I--targeted chemotherapy of human colon cancer in xenografts [2].
• The requirement of mouse DNA topoisomerase IIIalpha during early embryogenesis is discussed in terms of its plausible role in chromosome replication and its interaction with the RecQ/SGS1 family of DNA helicases, whose members include the Bloom's syndrome and the Werner's syndrome gene products [3].
• Effects of the bifunctional antitumor intercalator ditercalinium on DNA in mouse leukemia L1210 cells and DNA topoisomerase II [4].
• Previous studies have shown that DNA topoisomerase II enzyme activity and protein levels are reduced in cloned lines of Adriamycin-resistant P388 leukemia cells relative to drug-sensitive cells (Deffie et al., Cancer Res., 49: 58-62, 1989) [5].

High impact information on Top1

• DNA topoisomerase I, a nuclear enzyme important for solving topological problems arising during DNA replication and for other cellular functions, has been identified as a principal target of a plant alkaloid 20(S)-camptothecin [2].
• Treatment with DNA topoisomerase II inhibitors accelerated both the rHuTNF-mediated DNA fragmentation and the elevation in TRPM-2 messenger RNA levels [6].
• On the other hand, polyoma RNA and 5S RNA synthesis were inhibited by novobiocin in a way that suggested the requirement of a DNA topoisomerase II or DNA gyrase activity for the initiation of transcription [7].
• In vitro transcription by Xenopus oocytes RNA polymerase III requires a DNA topoisomerase II activity [7].
• Aberrant lamination in the cerebral cortex of mouse embryos lacking DNA topoisomerase IIbeta [8].

Chemical compound and disease context of Top1

• Decreased DNA topoisomerase II in daunorubicin-resistant Ehrlich ascites tumor cells [9].
• Inhibitors of bacterial DNA gyrase and eukaryotic DNA topoisomerase (novobiocin and nalidixic acid) were investigated with respect to their effect on the activity of RNA-dependent DNA polymerases from murine and avian retroviruses [10].
• Inhibition of protein synthesis reduces the cytotoxicity of 4'-(9-acridinylamino)methanesulfon-m-anisidide without affecting DNA breakage and DNA topoisomerase II in a murine mastocytoma cell line [11].
• The effects of various 9-aminoacridine derivatives differing by their DNA affinities and DNA sequence selectivity of binding were compared in the presence of purified mouse leukemia L1210 DNA topoisomerase II [12].
• Compared to a potent eukaryotic DNA topoisomerase type II poison, etoposide (VP-16, 0.5, 1 and 5 mg/kg body weight, given intraperitoneally), ciprofloxacin produced comparable dose-dependent SCE frequency increases [13].

Biological context of Top1

• The mouse cDNA encoding DNA topoisomerase I (TopoI) was cloned and the nucleotide sequence of 3512 bp was determined [14].
• Genetic mapping of DNA topoisomerase I-related sequences to mouse chromosomes 2 and 14 [15].
• We propose that FdUMP[10] damages DNA by trapping Top1 at uracil and FdU misincorporation sites resulting from thymidylate synthase inhibition and thymine depletion [16].
• Involvement of lysosomal cathepsins in the cleavage of DNA topoisomerase I during necrotic cell death [1].
• Neither the agents nor TNF alpha directly inhibits DNA topoisomerase II activity but both did cause decreased phosphorylation of the enzyme by protein kinase C (PKC) [17].

Anatomical context of Top1

• DNA topoisomerase I in the mouse central nervous system: Age and sex dependence [18].
• We also found that the amount of immunoreactive DNA topoisomerase II from these cells is about one-third that seen in the drug-sensitive cell line [9].
• This covalently linked protein has the same reduced molecular weight as purified calf thymus DNA topoisomerase II [19].
• DNA topoisomerase II content, as assayed by immunoblotting with a polyclonal rabbit anti-topoisomerase II antiserum, was virtually absent in nuclear extracts of quiescent CHO cells in contrast to logarithmically growing cells [20].
• Decreased expression of DNA topoisomerase I in camptothecin-resistant tumor cell lines as determined by a monoclonal antibody [21].

Associations of Top1 with chemical compounds

• In biochemical assay, Top1 is directly trapped at uracil and FdU misincorporation sites [16].
• Camptothecin-resistant P388/CPT45 cells lacking Top1 are cross-resistant to FdUMP[10] as well as to FdUMP, FdU, and the thymidylate synthase inhibitor raltitrexed (Tomudex) [16].
• Evidence for a mutant allele of the gene for DNA topoisomerase II in adriamycin-resistant P388 murine leukemia cells [5].
• However, under the same conditions, rHTNF markedly enhanced the cytotoxicity of Adriamycin, actinomycin D, 4'-(9-acridinylamino)-methanesulfon-m-anisidide, teniposide (VM 26), and etoposide (VP 16), all targeted at DNA topoisomerase II [22].
• 4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA) is a DNA intercalating 9-aminoacridine with clinical activity in adult acute leukemia. m-AMSA has been shown to produce protein-linked DNA strand breaks in mammalian cells through an interaction with the nuclear enzyme DNA topoisomerase II [23].

Regulatory relationships of Top1

• Impairment of Moloney murine leukemia virus integration in a cell line underexpressing DNA topoisomerase II [24].

Other interactions of Top1

• The Top-1 gene was also shown to be linked to the agouti locus [25].
• The disrupted Top-1 allele is embryonic lethal when homozygous, and development of such embryos fails between the 4- and 16-cell stages [25].
• When used in combination with interferon gamma (IFNG) or chemotherapeutic drugs targeted at DNA topoisomerase II, synergistic cytotoxicity has been observed [26].
• In contrast, the activity of DNA Topoisomerase I declined, corresponding to an increase in the PARP activity [27].
• Characterization of a DNA topoisomerase IIalpha gene rearrangement in adriamycin-resistant P388 leukemia: expression of a fusion messenger RNA transcript encoding topoisomerase IIalpha and the retinoic acid receptor alpha locus [28].

Analytical, diagnostic and therapeutic context of Top1

• In order to further characterize this enzyme in vivo, we have used gene targeting to inactivate the mouse Top-1 gene [25].
• The phosphorylation of DNA topoisomerase I in quiescent murine 3T3-L1 fibroblasts treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) was characterized by in vivo labeling with [32P] orthophosphate and immunoprecipitation with a scleroderma anti-DNA topoisomerase I autoantibody [29].
• Translocations of the MLL gene at chromosome band 11q23 are the most common cytogenetic alterations in de novo leukemia in infants and in leukemia related to chemotherapy with DNA topoisomerase II inhibitors [30].
• We have carried out immunofluorescence labelling of two human cell types, HeLa cells and peripheral blood lymphocytes, prepared by several different fixation/permeabilization protocols using a variety of antibodies against DNA Topoisomerase II (Topo II) [31].
• NC-190 and etoposide are inhibitors of DNA topoisomerase II, but there was no difference in cellular content of DNA topoisomerase II between the two cell lines as determined by Western blot analysis [32].

References