Effect of heliquinomycin on the activity of human minichromosome maintenance 4/6/7 helicase

The antibiotic heliquinomycin, which inhibits cellular DNA replication at a half-maximal inhibitory concentration (IC₅₀) of 1.4-4 μ m, was found to inhibit the DNA helicase activity of the human minichromosome maintenance (MCM) 4/6/7 complex at an IC₅₀ value of 2.4 μ m. In contrast, 14 μ m heliquino...

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Bibliographic Details
Published in:The FEBS journal 2009-06, Vol.276 (12), p.3382-3391
Main Authors: Ishimi, Yukio, Sugiyama, Takafumi, Nakaya, Ryou, Kanamori, Makoto, Kohno, Toshiyuki, Enomoto, Takemi, Chino, Makoto
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - antagonists & inhibitors
Adenosine Triphosphatases - metabolism
adenosinetriphosphatase
Antibiotics
anticancer drug
antigens
Benzoquinones - pharmacology
Biochemistry
Biological Transport - drug effects
Bromodeoxyuridine - metabolism
Cell Cycle Proteins - metabolism
Cellular biology
Deoxyribonucleic acid
DNA
DNA helicases
DNA Helicases - antagonists & inhibitors
DNA Helicases - metabolism
DNA Polymerase I - antagonists & inhibitors
DNA Polymerase I - metabolism
DNA Primase - antagonists & inhibitors
DNA Primase - metabolism
DNA replication
DNA-Binding Proteins - metabolism
Dose-Response Relationship, Drug
Enzymes
Exodeoxyribonucleases - antagonists & inhibitors
Exodeoxyribonucleases - metabolism
HeLa Cells
Humans
inhibitory concentration 50
MCM 4/6/7 helicase
Minichromosome Maintenance Complex Component 4
Minichromosome Maintenance Complex Component 6
Minichromosome Maintenance Complex Component 7
Molecular biology
Multiprotein Complexes - metabolism
Nuclear Proteins - metabolism
oligonucleotides
polymerization
Protein Binding - drug effects
RecQ Helicases - antagonists & inhibitors
RecQ Helicases - metabolism
Replication Protein A - metabolism
RNA
RNA - genetics
RNA - metabolism
Simian virus 40
single-stranded DNA
Spiro Compounds - pharmacology
Werner Syndrome Helicase
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Summary:The antibiotic heliquinomycin, which inhibits cellular DNA replication at a half-maximal inhibitory concentration (IC₅₀) of 1.4-4 μ m, was found to inhibit the DNA helicase activity of the human minichromosome maintenance (MCM) 4/6/7 complex at an IC₅₀ value of 2.4 μ m. In contrast, 14 μ m heliquinomycin did not inhibit significantly either the DNA helicase activity of the SV40 T antigen and Werner protein or the oligonucleotide displacement activity of human replication protein A. At IC₅₀ values of 25 and 6.5 μ m, heliquinomycin inhibited the RNA priming and DNA polymerization activities, respectively, of human DNA polymerase-α/primase. Thus, of the enzymes studied, the MCM4/6/7 complex was the most sensitive to heliquinomycin; this suggests that MCM helicase is one of the main targets of heliquinomycin in vivo. It was observed that heliquinomycin did not inhibit the ATPase activity of the MCM4/6/7 complex to a great extent in the absence of single-stranded DNA. In contrast, heliquinomycin at an IC₅₀ value of 5.2 μ m inhibited the ATPase activity of the MCM4/6/7 complex in the presence of single-stranded DNA. This suggests that heliquinomycin interferes with the interaction of the MCM4/6/7 complex with single-stranded DNA.
ISSN:1742-464X
1742-4658
DOI:10.1111/j.1742-4658.2009.07064.x