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Single-molecule observations of topotecan-mediated TopIB activity at a unique DNA sequence

The rate of DNA supercoil removal by human topoisomerase IB (TopIB) is slowed down by the presence of the camptothecin class of antitumor drugs. By preventing religation, these drugs also prolong the lifetime of the covalent TopIB–DNA complex. Here, we use magnetic tweezers to measure the rate of su...

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Autores principales: Koster, Daniel A., Czerwinski, Fabian, Halby, Ludovic, Crut, Aurélien, Vekhoff, Pierre, Palle, Komaraiah, Arimondo, Paola B., Dekker, Nynke H.
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2367732/
https://www.ncbi.nlm.nih.gov/pubmed/18292117
http://dx.doi.org/10.1093/nar/gkn035
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author Koster, Daniel A.
Czerwinski, Fabian
Halby, Ludovic
Crut, Aurélien
Vekhoff, Pierre
Palle, Komaraiah
Arimondo, Paola B.
Dekker, Nynke H.
author_facet Koster, Daniel A.
Czerwinski, Fabian
Halby, Ludovic
Crut, Aurélien
Vekhoff, Pierre
Palle, Komaraiah
Arimondo, Paola B.
Dekker, Nynke H.
author_sort Koster, Daniel A.
collection PubMed
description The rate of DNA supercoil removal by human topoisomerase IB (TopIB) is slowed down by the presence of the camptothecin class of antitumor drugs. By preventing religation, these drugs also prolong the lifetime of the covalent TopIB–DNA complex. Here, we use magnetic tweezers to measure the rate of supercoil removal by drug-bound TopIB at a single DNA sequence in real time. This is accomplished by covalently linking camptothecins to a triple helix-forming oligonucleotide that binds at one location on the DNA molecule monitored. Surprisingly, we find that the DNA dynamics with the TopIB–drug interaction restricted to a single DNA sequence are indistinguishable from the dynamics observed when the TopIB–drug interaction takes place at multiple sites. Specifically, the DNA sequence does not affect the instantaneous supercoil removal rate or the degree to which camptothecins increase the lifetime of the covalent complex. Our data suggest that sequence-dependent dynamics need not to be taken into account in efforts to develop novel camptothecins.
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spelling pubmed-23677322008-05-07 Single-molecule observations of topotecan-mediated TopIB activity at a unique DNA sequence Koster, Daniel A. Czerwinski, Fabian Halby, Ludovic Crut, Aurélien Vekhoff, Pierre Palle, Komaraiah Arimondo, Paola B. Dekker, Nynke H. Nucleic Acids Res Nucleic Acid Enzymes The rate of DNA supercoil removal by human topoisomerase IB (TopIB) is slowed down by the presence of the camptothecin class of antitumor drugs. By preventing religation, these drugs also prolong the lifetime of the covalent TopIB–DNA complex. Here, we use magnetic tweezers to measure the rate of supercoil removal by drug-bound TopIB at a single DNA sequence in real time. This is accomplished by covalently linking camptothecins to a triple helix-forming oligonucleotide that binds at one location on the DNA molecule monitored. Surprisingly, we find that the DNA dynamics with the TopIB–drug interaction restricted to a single DNA sequence are indistinguishable from the dynamics observed when the TopIB–drug interaction takes place at multiple sites. Specifically, the DNA sequence does not affect the instantaneous supercoil removal rate or the degree to which camptothecins increase the lifetime of the covalent complex. Our data suggest that sequence-dependent dynamics need not to be taken into account in efforts to develop novel camptothecins. Oxford University Press 2008-04 2008-02-21 /pmc/articles/PMC2367732/ /pubmed/18292117 http://dx.doi.org/10.1093/nar/gkn035 Text en © 2008 The Author(s) http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Nucleic Acid Enzymes
Koster, Daniel A.
Czerwinski, Fabian
Halby, Ludovic
Crut, Aurélien
Vekhoff, Pierre
Palle, Komaraiah
Arimondo, Paola B.
Dekker, Nynke H.
Single-molecule observations of topotecan-mediated TopIB activity at a unique DNA sequence
title Single-molecule observations of topotecan-mediated TopIB activity at a unique DNA sequence
title_full Single-molecule observations of topotecan-mediated TopIB activity at a unique DNA sequence
title_fullStr Single-molecule observations of topotecan-mediated TopIB activity at a unique DNA sequence
title_full_unstemmed Single-molecule observations of topotecan-mediated TopIB activity at a unique DNA sequence
title_short Single-molecule observations of topotecan-mediated TopIB activity at a unique DNA sequence
title_sort single-molecule observations of topotecan-mediated topib activity at a unique dna sequence
topic Nucleic Acid Enzymes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2367732/
https://www.ncbi.nlm.nih.gov/pubmed/18292117
http://dx.doi.org/10.1093/nar/gkn035
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