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Nucleic Acids Research Advance Access published online on July 24, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn466
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© 2008 The Author(s)
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.

Nucleic Acid Enzymes

Human topoisomerase II{alpha} uses a two-metal-ion mechanism for DNA cleavage

Joseph E. Deweese1, Alex B. Burgin2 and Neil Osheroff1,3,*

1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, 2deCODE biostructures, Bainbridge Island, WA 98110, USA and 3Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, TN 37232-0146

*To whom correspondence should be addressed: Tel: +1 615 322 4338; Fax: +1 615 343 1166; Email: neil.osheroff{at}vanderbilt.edu

Received May 20, 2008. Revised July 2, 2008. Accepted July 3, 2008.

The DNA cleavage reaction of human topoisomerase II{alpha} is critical to all of the physiological and pharmacological functions of the protein. While it has long been known that the type II enzyme requires a divalent metal ion in order to cleave DNA, the role of the cation in this process is not known. To resolve this fundamental issue, the present study utilized a series of divalent metal ions with varying thiophilicities in conjunction with DNA cleavage substrates that replaced the 3'-bridging oxygen of the scissile bond with a sulfur atom (i.e. 3'-bridging phosphorothiolates). Rates and levels of DNA scission were greatly enhanced when thiophilic metal ions were included in reactions that utilized sulfur-containing substrates. Based on these results and those of reactions that employed divalent cation mixtures, we propose that topoisomerase II{alpha} mediates DNA cleavage via a two-metal-ion mechanism. In this model, one of the metal ions makes a critical interaction with the 3'-bridging atom of the scissile phosphate. This interaction greatly accelerates rates of enzyme-mediated DNA cleavage, and most likely is needed to stabilize the leaving 3'-oxygen.


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