The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs
Joint Authors
Gmeiner, William H.
Salsbury, Freddie
Marky, Luis A.
Olsen, Chris M.
Source
Issue
Vol. 2011, Issue 2011 (31 Dec. 2011), pp.1-8, 8 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2011-08-28
Country of Publication
Egypt
No. of Pages
8
Main Subjects
Abstract EN
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.
American Psychological Association (APA)
Gmeiner, William H.& Salsbury, Freddie& Olsen, Chris M.& Marky, Luis A.. 2011. The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs. Journal of Nucleic Acids،Vol. 2011, no. 2011, pp.1-8.
https://search.emarefa.net/detail/BIM-486643
Modern Language Association (MLA)
Gmeiner, William H.…[et al.]. The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs. Journal of Nucleic Acids No. 2011 (2011), pp.1-8.
https://search.emarefa.net/detail/BIM-486643
American Medical Association (AMA)
Gmeiner, William H.& Salsbury, Freddie& Olsen, Chris M.& Marky, Luis A.. The Stability of a Model Substrate for Topoisomerase 1-Mediated DNA Religation Depends on the Presence of Mismatched Base Pairs. Journal of Nucleic Acids. 2011. Vol. 2011, no. 2011, pp.1-8.
https://search.emarefa.net/detail/BIM-486643
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-486643