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Nucleic Acids Research 2006 34(5):1597-1607; doi:10.1093/nar/gkl057
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Published online 20 March 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Article

mAMSA resistant human topoisomerase IIß mutation G465D has reduced ATP hydrolysis activity

Kathryn L. Gilroy, Chrysoula Leontiou, Kay Padget, Jeremy H. Lakey and Caroline A. Austin*

The Institute for Cell and Molecular Biosciences, The University of Newcastle upon Tyne Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

*To whom correspondence should be addressed. Tel: +44 191 222 5251; Fax: +44 191 222 7424; Email: caroline.austin{at}ncl.ac.uk

Received February 2, 2006. Accepted February 24, 2006.

Type II Human DNA Topoisomerases (topos II) play an essential role in DNA replication and transcription and are important targets for cancer chemotherapeutic drugs. Topoisomerase II causes transient double-strand breaks in DNA, forming a gate through which another double helix is passed, and acts as a DNA dependent ATPase. Mutations in topoII have been linked to atypical multi-drug resistance. Both human Topoisomerase II isoforms, {alpha} and ß, are targeted by amsacrine. We have used a forced molecular evolution approach to identify mutations conferring resistance to acridines. Here we report mutation ßG465D, which was selected with mAMSA and DACA and is cross-resistant to etoposide, ellipticine and doxorubicin. Resistance to mAMSA appears to decrease over time indicating a previously unreported resistance mechanism. G465D lies within the B' domain in the region that contacts the cleaved gate helix. There is a 3-fold decrease in ATP affinity and ATP hydrolysis and an altered requirement for magnesium in decatenation assays. The decatenation rate is decreased for the mutated G465D protein. And we report for the first time the use of fluorescence anisotropy with intact human topoisomerase II.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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C. Leontiou, G. P. Watters, K. L. Gilroy, P. Heslop, I. G. Cowell, K. Craig, R. N. Lightowlers, J. H. Lakey, and C. A. Austin
Differential Selection of Acridine Resistance Mutations in Human DNA Topoisomerase IIbeta Is Dependent on the Acridine Structure
Mol. Pharmacol., April 1, 2007; 71(4): 1006 - 1014.
[Abstract] [Full Text] [PDF]


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