Effects of the DNA intercalators 4'-(9-acridinylamino)methanesulfon-m-anisidide and 2-methyl-9-hydroxyellipticinium on topoisomerase II mediated DNA strand cleavage and strand passage

Yeast temperature-sensitive mutants of DNA topoisomerase II are incapable of chromosome condensation and anaphase chromatid segregation. In mammalian cells, topoisomerase II inhibitors such as etoposide (VP-16-123) have similar effects. Unfortunately, conclusions drawn from work with mammalian cells have been limited by the fact that the standard inhibitors of topoisomerase II also generate DNA strand breaks, which when produced by other agents (e.g. ionizing radiation) are known to affect progression into and through mitosis. Here we show that the anti-tumour agent ICRF-193, recently identified as a topoisomerase II inhibitor operating by a non-standard mechanism, generates neither covalent complexes between topoisomerase II and DNA, nor adjacent DNA strand breaks, in mitotic HeLa. However, the drug does prevent anaphase segregation in HeLa and PtK2 cells, with effects similar to those of etoposide. We therefore conclude that topoisomerase II function is required for anaphase chromosome segregation in mammalian cells, as it is in yeast.

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DNA Repair Functions That Control Sensitivity to Topoisomerase-Targeting Drugs

Eukaryotic Cell ◽

10.1128/ec.3.1.82-90.2004 ◽

2004 ◽

Vol 3 (1) ◽

pp. 82-90 ◽

Cited By ~ 39

Author(s):

Mobeen Malik ◽

John L. Nitiss

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Topoisomerase I ◽

Topoisomerase Ii ◽

Excision Repair ◽

Dna Strand Breaks ◽

Dna Topology ◽

Strand Breaks ◽

Wide Range ◽

Dna Strand

ABSTRACT DNA topoisomerases play critical roles in a wide range of cellular processes by altering DNA topology to facilitate replication, transcription, and chromosome segregation. Topoisomerases alter DNA topology by introducing transient DNA strand breaks that involve a covalent protein DNA intermediate. Many agents have been found to prevent the religation of DNA strand breaks induced by the enzymes, thereby converting the enzymes into DNA-damaging agents. Repair of the DNA damage induced by topoisomerases is significant in understanding drug resistance arising following treatment with topoisomerase-targeting drugs. We have used the fission yeast Schizosaccharomyces pombe to identify DNA repair pathways that are important for cell survival following drug treatment. S. pombe strains carrying mutations in genes required for homologous recombination such as rad22A or rad32 (homologues of RAD52 and MRE11) are hypersensitive to drugs targeting either topoisomerase I or topoisomerase II. In contrast to results observed with Saccharomyces cerevisiae, S. pombe strains defective in nucleotide excision repair are also hypersensitive to topoisomerase-targeting agents. The loss of DNA replication or DNA damage checkpoints also sensitizes cells to both topoisomerase I and topoisomerase II inhibitors. Finally, repair genes (such as the S. pombe rad8+ gene) with no obvious homologs in other systems also play important roles in causing sensitivity to topoisomerase drugs. Since the pattern of sensitivity is distinct from that seen with other systems (such as the S. cerevisiae system), our results highlight the usefulness of S. pombe in understanding how cells deal with the unique DNA damage induced by topoisomerases.

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Coupling ATP hydrolysis to DNA strand passage in type IIA DNA topoisomerases

Biochemical Society Transactions ◽

10.1042/bst20051460 ◽

2005 ◽

Vol 33 (6) ◽

pp. 1460 ◽

Cited By ~ 8

Author(s):

L. Costenaro ◽

A. Maxwell ◽

S. Mitelheiser ◽

A.D. Bates

Keyword(s):

Atp Hydrolysis ◽

Dna Topoisomerases ◽

Dna Strand ◽

Strand Passage

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DESIGN, SYNTHESIS, MOLECULAR DOCKING AND ANTI-PROLIFERATIVE EVALUATION OF NOVEL PYRAZOLO[4,3-E][1,2,4]TRIAZOLO[4,3-C]PYRIMIDINE DERIVATIVES AS POTENTIAL DNA INTERCALATORS AND TOPOISOMERASE II INHIBITORS

Al-Azhar Journal of Pharmaceutical Sciences ◽

10.21608/ajps.2020.86011 ◽

2020 ◽

Vol 61 (1) ◽

pp. 12-28

Author(s):

Farag Sherbiny

Keyword(s):

Molecular Docking ◽

Topoisomerase Ii ◽

Pyrimidine Derivatives ◽

Design Synthesis ◽

Dna Intercalators ◽

Topoisomerase Ii Inhibitors

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Visualization of DNA and DNA-protein complexes by TEM

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100162442 ◽

1990 ◽

Vol 48 (3) ◽

pp. 970-970

Author(s):

Jack D. Griffith

Keyword(s):

Topoisomerase Ii ◽

Structural Information ◽

Protein Complexes ◽

Reca Protein ◽

Biochemical Processes ◽

Reverse Transcriptase Enzyme ◽

Dna Strand Exchange ◽

Nmr Techniques ◽

Image Averaging ◽

Dna Strand

A large class of DNA and DNA-protein complexes of great interest to modern molecular biologists lie in a realm of size and complexity that it is too large for structural approaches using X ray diffraction or NMR techniques. Such complexes are usually highly irregular so that EM methods employing the formation of 2 dimensional crystals or dense-packing followed by image averaging are not usable. Examples of such complexes include topoisomerase II heterodimers bound to supercoiled DNA, plasmid DNAs being replicated by the battery of nearly 20 different proteins that initiate and carry out replication in E. coli, complexes of reverse transcriptase enzyme degrading the RNA strand of an RNA/DNA hybrid duplex, and many of the recombinational intermediates of DNA strand exchanges. In the latter complexes large protein scaffolds built of hundreds of RecA protein monomers form filaments with in which the events of DNA strand exchange occur.To visualize such large and complex structures the demands of the biochemical reactions must be given first prior ity: is ATP, glycerol, or salt required for the on going reactions? Do the reactions occur at room temperature or only at 37 degrees? Efforts in this laboratory have been focused on determining which of the various routes for visualizing macromolecules provides the best general approach to obtaining useful structural information that can be directly related to the biochemical processes.

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