DNA STRAND-BREAKS INDUCED BY THE TOPOISOMERASE I INHIBITOR CAMPTOTHECIN IN UNSTIMULATED HUMAN WHITE BLOOD CELLS

2002 ◽  
Vol 26 (8) ◽  
pp. 707-713 ◽  
Author(s):  
P Daza
Keyword(s):  
Blood Cells ◽  
Topoisomerase I ◽  
White Blood Cells ◽  
Dna Strand Breaks ◽  
Strand Breaks ◽  
Topoisomerase I Inhibitor ◽  
Dna Strand ◽  
Human White Blood Cells

scholarly journals DNA Repair Functions That Control Sensitivity to Topoisomerase-Targeting Drugs

2004 ◽  
Vol 3 (1) ◽  
pp. 82-90 ◽  
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.

scholarly journals Inhibition of replicon initiation in human cells following stabilization of topoisomerase-DNA cleavable complexes.

1991 ◽  
Vol 11 (7) ◽  
pp. 3711-3718 ◽  
Author(s):  
W K Kaufmann ◽  
J C Boyer ◽  
L L Estabrooks ◽  
S J Wilson
Keyword(s):  
Ataxia Telangiectasia ◽  
Topoisomerase I ◽  
Cellular Response ◽  
Human Fibroblasts ◽  
Dna Strand Breaks ◽  
Velocity Sedimentation ◽  
Type I ◽  
Dna Topoisomerase ◽  
Strand Breaks ◽  
Dna Strand

Diploid human fibroblast strains were treated for 10 min with inhibitors of type I and type II DNA topoisomerases, and after removal of the inhibitors, the rate of initiation of DNA synthesis at replicon origins was determined. By alkaline elution chromatography, 4'-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine), an inhibitor of DNA topoisomerase II, was shown to produce DNA strand breaks. These strand breaks are thought to reflect drug-induced stabilization of topoisomerase-DNA cleavable complexes. Removal of the drug led to a rapid resealing of the strand breaks by dissociation of the complexes. Velocity sedimentation analysis was used to quantify the effects of amsacrine treatment on DNA replication. It was demonstrated that transient exposure to low concentrations of amsacrine inhibited replicon initiation but did not substantially affect DNA chainelongation within operating replicons. Maximal inhibition of replicon initiation occurred 20 to 30 min after drug treatment, and the initiation rate recovered 30 to 90 min later. Ataxia telangiectasia cells displayed normal levels of amsacrine-induced DNA strand breaks during stabilization of cleavable complexes but failed to downregulate replicon initiation after exposure to the topoisomerase inhibitor. Thus, inhibition of replicon initiation in response to DNA damage appears to be an active process which requires a gene product which is defective or missing in ataxia telangiectasia cells. In normal human fibroblasts, the inhibition of DNA topoisomerase I by camptothecin produced reversible DNA strand breaks. Transient exposure to this drug also inhibited replicon initiation. These results suggest that the cellular response pathway which downregulates replicon initiation following genotoxic damage may respond to perturbations of chromatin structure which accompany stabilization of topoisomerase-DNA cleavable complexes.

Positive Association Between DNA Strand Breaks in Peripheral Blood Mononuclear Cells and Polyunsaturated Fatty Acids in Red Blood Cells From Women

2007 ◽  
Vol 59 (1) ◽  
pp. 21-28 ◽  
Author(s):  
Audur Y. Thorlaksdottir ◽  
Jon J. Jonsson ◽  
Laufey Tryggvadottir ◽  
Gudrun V. Skuladottir ◽  
Anna L. Petursdottir ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Peripheral Blood Mononuclear Cells ◽  
Blood Cells ◽  
Mononuclear Cells ◽  
Positive Association ◽  
Dna Strand Breaks ◽  
Peripheral Blood Mononuclear ◽  
Strand Breaks ◽  
Blood Mononuclear Cells ◽  
Dna Strand
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