The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs
Topoisomerase 1 (Top1) enzymes regulate DNA superhelicity by forming covalent cleavage complexes that undergo controlled rotation. Substitution of nucleoside analogs at the +1 position of the DNA duplex relative to the Top1 cleavage site inhibits DNA religation. The reduced efficiency for Top1-medi...
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| Format: | Article |
| Language: | English |
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Wiley
2011-01-01
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| Series: | Journal of Nucleic Acids |
| Online Access: | http://dx.doi.org/10.4061/2011/631372 |
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| author | William H. Gmeiner Freddie Salsbury Chris M. Olsen Luis A. Marky |
| author_facet | William H. Gmeiner Freddie Salsbury Chris M. Olsen Luis A. Marky |
| author_sort | William H. Gmeiner |
| collection | DOAJ |
| description | Topoisomerase 1 (Top1) enzymes regulate DNA superhelicity by forming covalent cleavage complexes that undergo controlled
rotation. Substitution of nucleoside analogs at the +1 position of the DNA duplex relative to the Top1 cleavage site inhibits DNA religation. The reduced efficiency for Top1-mediated religation contributes to the anticancer activity of widely used anticancer drugs including fluoropyrimidines and gemcitabine. In the present study, we report that mismatched base pairs at the +1 position destabilize the duplex DNA components for a model Top1 cleavage complex formation even though one duplex component does not directly include a mismatched base pair. Molecular dynamics simulations reveal G-dU and G-FdU mismatched base pairs, but not a G-T mismatched base pair, increase flexibility at the Top1 cleavage site, and affect coupling between the regions required for the religation reaction to occur. These results demonstrate that substitution of dT analogs into the +1 position of the non-scissile strand alters the stability and flexibility of DNA contributing to the reduced efficiency for Top1-mediated DNA religation. These effects are inherent in the DNA duplex and do not require formation of the Top1:DNA complex. These results provide a biophysical rationale for the inhibition of Top1-mediated DNA religation by nucleotide analog substitution. |
| format | Article |
| id | doaj-art-750e52c6bb934f349072ab7d61525691 |
| institution | Kabale University |
| issn | 2090-021X |
| language | English |
| publishDate | 2011-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Nucleic Acids |
| spelling | doaj-art-750e52c6bb934f349072ab7d615256912025-02-03T01:24:05ZengWileyJournal of Nucleic Acids2090-021X2011-01-01201110.4061/2011/631372631372The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base PairsWilliam H. Gmeiner0Freddie Salsbury1Chris M. Olsen2Luis A. Marky3Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USADepartment of Physics, Wake Forest University, Winston-Salem, NC 27109, USADepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USATopoisomerase 1 (Top1) enzymes regulate DNA superhelicity by forming covalent cleavage complexes that undergo controlled rotation. Substitution of nucleoside analogs at the +1 position of the DNA duplex relative to the Top1 cleavage site inhibits DNA religation. The reduced efficiency for Top1-mediated religation contributes to the anticancer activity of widely used anticancer drugs including fluoropyrimidines and gemcitabine. In the present study, we report that mismatched base pairs at the +1 position destabilize the duplex DNA components for a model Top1 cleavage complex formation even though one duplex component does not directly include a mismatched base pair. Molecular dynamics simulations reveal G-dU and G-FdU mismatched base pairs, but not a G-T mismatched base pair, increase flexibility at the Top1 cleavage site, and affect coupling between the regions required for the religation reaction to occur. These results demonstrate that substitution of dT analogs into the +1 position of the non-scissile strand alters the stability and flexibility of DNA contributing to the reduced efficiency for Top1-mediated DNA religation. These effects are inherent in the DNA duplex and do not require formation of the Top1:DNA complex. These results provide a biophysical rationale for the inhibition of Top1-mediated DNA religation by nucleotide analog substitution.http://dx.doi.org/10.4061/2011/631372 |
| spellingShingle | William H. Gmeiner Freddie Salsbury Chris M. Olsen Luis A. Marky The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs Journal of Nucleic Acids |
| title | The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs |
| title_full | The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs |
| title_fullStr | The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs |
| title_full_unstemmed | The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs |
| title_short | The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs |
| title_sort | stability of a model substrate for topoisomerase 1 mediated dna religation depends on the presence of mismatched base pairs |
| url | http://dx.doi.org/10.4061/2011/631372 |
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