Disruption of a topoisomerase-DNA cleavage complex by a DNA helicase.
The type II DNA topoisomerases are targets for a variety of chemotherapeutic agents, including the antibacterial quinolones and several families of antitumor drugs. These agents stabilize an enzyme-DNA cleavage complex that consists of the topoisomerase covalently linked to the 5' phosphates of a double-stranded DNA break. Although the drug-stabilized cleavage complex is readily reversible, it can result in cell death by a mechanism that remains uncertain. Here we demonstrate that the action of a DNA helicase can convert the cleavage complex into a nonreversible DNA break by displacing DNA strands from the complex. Formation of a nonreversible DNA break, induced by a DNA helicase, could explain the cytotoxicity of these topoisomerase poisons.
Howard
M T
MT
Department of Biology, University of North Carolina, Chapel Hill 27599.
Neece
S H
SH
Matson
S W
SW
Kreuzer
K N
KN
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000677:Amsacrine; D017122:Bacteriophage T4 / Q000201:enzymology; D001483:Base Sequence; D004265:DNA Helicases; D004250:DNA Topoisomerases, Type II / Q000302:isolation & purification / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli / Q000201:enzymology; D008961:Models, Structural; D008969:Molecular Sequence Data; D010957:Plasmids / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D013379:Substrate Specificity
D000677:Amsacrine; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; D004250:DNA Topoisomerases, Type II