scholarly journals DNA topoisomerase II selects DNA cleavage sites based on reactivity rather than binding affinity

2007 ◽  
Vol 35 (11) ◽  
pp. 3764-3773 ◽  
Author(s):  
Felix Mueller-Planitz ◽  
Daniel Herschlag
Keyword(s):  
Binding Affinity ◽  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Cleavage Sites ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase

Altered catalytic activity of and DNA cleavage by DNA topoisomerase II from human leukemic cells selected for resistance to VM-26

Biochemistry ◽  
1988 ◽  
Vol 27 (24) ◽  
pp. 8861-8869 ◽  
Author(s):  
Mary K. Danks ◽  
Carla A. Schmidt ◽  
Margaret C. Cirtain ◽  
D. Parker Suttle ◽  
William T. Beck
Keyword(s):  
Catalytic Activity ◽  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Leukemic Cells ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Human Leukemic Cells

scholarly journals Coupling between ATP Binding and DNA Cleavage by DNA Topoisomerase II

2008 ◽  
Vol 283 (25) ◽  
pp. 17463-17476 ◽  
Author(s):  
Felix Mueller-Planitz ◽  
Daniel Herschlag
Keyword(s):  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Atp Binding ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase

scholarly journals Cytotoxicity and inhibitory properties against topoisomerase II of doxorubicin and its formamidine derivatives.

2009 ◽  
Vol 56 (1) ◽  
Author(s):  
Krzysztof Kik ◽  
Kazimierz Studzian ◽  
Małgorzata Wasowska-Łukawska ◽  
Irena Oszczapowicz ◽  
Leszek Szmigiero
Keyword(s):  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Colorimetric Assay ◽  
Cellular Level ◽  
Cytotoxic Action ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Free System ◽  
Cell Free System ◽  
Pbr322 Dna

This work was undertaken to compare cytotoxicity, DNA damaging properties and effect on DNA cleavage by topoisomerase II of the anthracycline drug doxorubicin (DOX) and its two derivatives with a formamidino group containing a cyclic amine moiety such as morpholine (DOXM) or hexamethyleneimine (DOXH). The tetrazolium dye colorimetric assay was used to determine the cytotoxic activity of anthracyclines toward L1210 leukemia cells. DNA damage was measured by alkaline elution technique. The effect of anthracyclines on DNA cleavage was studied in a cell-free system containing supercoiled pBR322 DNA and purified human topoisomerase II. The cytotoxicity data and the results of studies on the mechanism of DNA break formation by anthracyclines at the cellular level and in the cell-free system showed that the presence of the formamidino group in the doxorubicin molecule reduced its ability to stimulate DNA cleavage by DNA topoisomerase II. DNA topoisomerase II is not a primary cellular target for DOXM or DOXH. An advantageous feature of formamidinoanthracyclines is their mechanism of cytotoxic action which is not related to the inhibition of DNA topoisomerase II. Therefore this class of anthracyclines seems to be a good source for selection of an anticancer drug directed toward cancer cells with the developed multidrug resistance attributed to the presence of altered DNA topoisomerase II.

Amsacrine-promoted DNA cleavage site determinants for the two human DNA topoisomerase II isoforms α and β

1996 ◽  
Vol 52 (11) ◽  
pp. 1675-1685 ◽  
Author(s):  
Katherine L. Marsh ◽  
Elaine Willmore ◽  
Stella Tinelli ◽  
Mariagrazia Cornarotti ◽  
Emma L. Meczes ◽  
...  
Keyword(s):  
Dna Cleavage ◽  
Cleavage Site ◽  
Topoisomerase Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Human Dna

Reduced DNA topoisomerase II activity and drug-stimulated DNA cleavage in 9-hydroxyellipticine resistant cells

1988 ◽  
Vol 37 (11) ◽  
pp. 2145-2149 ◽  
Author(s):  
Jean-Yves Charcosset ◽  
Jean-Marie Saucier ◽  
Alain Jacquemin-Sablon
Keyword(s):  
Dna Cleavage ◽  
Topoisomerase Ii ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Resistant Cells

NUP98 Translocation Breakpoints in Treatment-Related MDS Are Drug-Stimulated DNA Topoisomerase II Cleavage Sites.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1970-1970
Author(s):  
Christos P. Kolaris ◽  
Mingli Liu ◽  
Katie Foote ◽  
Peter D. Aplan ◽  
Harish G. Ahuja ◽  
...  
Keyword(s):  
Topoisomerase Ii ◽  
Chromosome Band ◽  
Nuclear Pore ◽  
Cleavage Sites ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Catalytic Inhibitor ◽  
Translocation Breakpoints ◽  
Dose Dependent

Abstract Chemotherapeutic DNA topoisomerase II (top2) poisons (i.e. agents that stabilize the top2 covalent complex and have the overall effect of increasing cleavage complexes) have been implicated in the treatment complication of leukemia characterized by balanced translocations, among which are translocations of the NUP98 gene at chromosome band 11p15. NUP98, which encodes a 98-kd docking protein in the nuclear pore complex, is disrupted by translocations in de novo and chemotherapy-related leukemias and has ~15 partner genes encoding proteins of diverse function. There have been no studies to delineate the mechanism whereby top2 poisons result in DNA damage leading to NUP98 translocations. Previously we described the TOP1 gene at chromosome band 20q11 as a recurring partner gene of NUP98 in 2 cases of treatment-related MDS (Ahuja 2000). The first patient was treated 9 years before for ALL with therapy including doxorubicin (ADR), daunorubicin and etoposide (VP). The second patient received VP and ADR in therapy for non-Hodgkin’s lymphoma and MDS was diagnosed 14 months after the primary cancer. In both cases, the NUP98 breakpoints were in intron 13 and the TOP1 breakpoints were in intron 7, though at distinct locations (Ahuja 2000). Sequencing of the breakpoint junctions on both derivative chromosomes showed near-precise recombinations relative to the germline sequences, indicating that the translocation breakpoints were at the sites of damage. Here, to interrogate whether drugs to which the patients were exposed stimulated formation of top2 cleavage complexes at these sites of damage, DNA substrates from germline NUP98 and TOP1 sequences were utilized in top2 in vitro cleavage assays, which entail trapping the cleavage complexes and mapping the cleavage sites in the sequence. ADR was examined over a range of concentrations because of its known effects of cleavage stimualtion at low concentrations and, at high concentrations, top2 catalytic inhibition due to intercalation. Etoposide and its catechol and quinone metabolites stimulated strong, heat stable top2 cleavage at several sites proximal to the NUP98 and TOP1 translocation breakpoints. At low concentration (~0.01μM) ADR also enhanced cleavage in a NUP98 substrate at several sites near the translocation breakpoint while dose-dependent cleavage diminution occurred at higher concentrations. Dose-response experiments with ADR are in progress using TOP1 substrates. Prior models based on the coincidence of in vitro top2 cleavage sites with cloned translocation breakpoints in MLL and partner genes or in PML and RARA and feasibility of resolution of the cleavage sites to form the respective breakpoint junctions have suggested drug-stimulated top2 cleavage as the relevant damage mechanism in other translocations (Whitmarsh 2003; Mistry 2003). The results of the present study support a model in which the chromosomal breakage leading to chemotherapy-related NUP98-TOP1 translocations is a consequence of drug-stimulated top2 cleavage also. Dose-dependent dual effects of ADR as a poison and a catalytic inhibitor of top2 function with respect to the sequence of a specific leukemia-associated gene have implications for its role in the genesis of translocations.

A method for the purification of DNA/protein complexes applied to DNA topoisomerase II cleavage sites

1991 ◽  
Vol 193 (1) ◽  
pp. 101-111 ◽  
Author(s):  
R.J. Anderson ◽  
C. Delgado ◽  
D. Fisher ◽  
J.M. Cunningham ◽  
G.E. Francis
Keyword(s):  
Topoisomerase Ii ◽  
Protein Complexes ◽  
Cleavage Sites ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase
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