Disease relevance of Top2

• This similarity in cleavage site structure for Drosophila topoisomerase II and E. coli DNA gyrase suggests that they share some fundamental features in their mechanism of action [1].
• We have isolated the gene coding for the Drosophila type II DNA topoisomerase by immunochemically screening a Drosophila cDNA library constructed with a phage lambda expression vector, lambda gt11 [2].
• Alterations in this gene are reported in approximately 5-10% of acute leukemias (AL) and characterize different leukemic subtypes such as infant (< 12 months of age) AL, topoisomerase II inhibitors-related (TR) AL and a small subset of de novo AML and ALL [3].
• In adult accessory glands as well as third instar larval neural ganglion and imaginal disk nuclei, DNA topoisomerase II shows areas of co-localization with chromatin adjacent to areas of extrachromosomal distribution [4].

High impact information on Top2

• Colocalization and biochemical experiments indicate that Barren associates with Topoisomerase II throughout mitosis and alters the activity of Topoisomerase II [5].
• Chromatid segregation at anaphase requires the barren product, a novel chromosome-associated protein that interacts with Topoisomerase II [5].
• The localization of topoisomerase II (topo II) in vivo was studied by recording time-lapse, three-dimensional data sets of living Drosophila melanogaster embryos injected with rhodamine-labeled topo II [6].
• Spo11 and MEI-W68 are members of a family of proteins similar to a novel type II topoisomerase [7].
• Chromosomes are highly undercondensed, particularly in the euchromatin, but nevertheless contain phosphorylated histone H3, condensin, and topoisomerase II [8].

Biological context of Top2

• The total histone mRNA was exclusively associated with DNA replication but, in contrast to top2 mRNA, mitotic and endoreplicating cells contained similar expression levels with no expression in the gonads [9].
• During gastrulation, top2 mRNA became differentially localized only to regions of DNA replication, including new expression in the gonads preceding mitosis/meiosis [9].
• Expression patterns for topoisomerase I and topoisomerase II during the embryogenesis of Drosophila melanogaster were compared with patterns of DNA replication and expression of the histone genes [9].
• In late oogenesis the maternally supplied top2 mRNA was evenly distributed throughout the egg with elevated levels at the posterior tip, a pattern that is maintained in syncytial blastoderm embryos [9].
• In addition, we have identified an unusual type of topoisomerase II binding site that is preferentially associated with the 5' ends of inactive hsp70 and actin genes, suggesting that this enzyme may facilitate changes in chromatin structure that are associated with repression of gene transcription [10].

Anatomical context of Top2

• In situ localization of DNA topoisomerase II, a major polypeptide component of the Drosophila nuclear matrix fraction [11].
• Similar immunocytochemical studies performed with permeabilized whole giant cells from third-instar larval salivary glands have shown topoisomerase II to be largely restricted to the polytene chromosomes [11].
• Protein kinase C phosphorylates topoisomerase II: topoisomerase activation and its possible role in phorbol ester-induced differentiation of HL-60 cells [12].
• A correlation between reduced expression of Gadd45 and increased resistance to topoisomerase I and topoisomerase II inhibitors in a variety of human cell lines was also found [13].
• Structure and partial amino acid sequence of calf thymus DNA topoisomerase II: comparison with other type II enzymes [14].

Associations of Top2 with chemical compounds

• About 0.85 mol of phosphate could be incorporated per mol of topoisomerase II, with phosphoserine as the only phospho amino acid produced [12].
• Inhibition of eukaryotic topoisomerase II by ultraviolet-induced cyclobutane pyrimidine dimers [15].
• Results of the present study demonstrate that the repair of cyclobutane pyrimidine dimers is important for the efficient catalytic function of topoisomerase II [15].
• We confirm that the alkylation of DNA by psorospermin takes place at N-7 of guanine in the presence of topoisomerase II, because substitution of the target guanine by 7-deazaguanine prevents alkylation [16].
• Analysis of a core domain in Drosophila DNA topoisomerase II. Targeting of an antitumor agent ICRF-159 [17].

Physical interactions of Top2

• SCF binds directly to topoisomerase II [18].

Regulatory relationships of Top2

• There was a similar preferential association of topoisomerase II with the 5' ends of transcriptionally repressed actin 5C and 57A genes [10].
• Since ATP hydrolysis is a prerequisite for enzyme turnover, it is concluded that phosphorylation modulates the overall catalytic activity of topoisomerase II by stimulating the enzyme's ATPase activity [19].

Other interactions of Top2

• The partial amino acid sequence of p140 calf thymus DNA topoisomerase II was determined by analysis of cyanogen bromide peptides [14].
• Phosphorylation stimulated the DNA relaxation activity of topoisomerase II by 3-fold over that of the dephosphorylated enzyme, and the effects of modification could be reversed by treatment with alkaline phosphatase [20].
• The loss of CAP-D2 after RNAi has additional downstream consequences on the stability of CAP-H, the localization of DNA topoisomerase II and other condensin subunits, and chromosome segregation [21].
• Immunoprecipitation suggests that the 30-kDa protein interacts with topoisomerase II in the nucleus, and hence that it is a functional form of SCF [22].
• To determine whether other protein kinases use a similar mechanism to activate the enzyme, the effects of protein kinase C mediated phosphorylation on the individual steps of the topoisomerase II catalytic cycle were assessed [23].

Analytical, diagnostic and therapeutic context of Top2

• DNA topoisomerase II (topo II) is thought to be a nuclear enzyme; during interphase most was insoluble and could be recovered in the pellet after centrifugation of cell homogenates at 10,000 g (P-10) [24].
• DNA topoisomerase II (Topo II) is a major component of mitotic chromosomes and an important drug target in cancer chemotherapy, however, its role in chromosome structure and dynamics remains controversial [25].
• Here we describe a micromanipulation experiment in which we follow in real time a single Drosophila melanogaster topoisomerase II acting on a linear DNA molecule which is mechanically stretched and supercoiled [26].
• Indirect immunofluorescence analyses of larval cryosections have confirmed the nuclear localization of topoisomerase II in situ [11].
• The binding of purified Drosophila topoisomerase II to the highly bent DNA segments from the SV40 terminus of replication and C. fasciculata kinetoplast minicircle DNA (kDNA) was examined using electron microscopy (EM) [27].

References