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Originally published In Press as doi:10.1074/jbc.M011143200 on February 23, 2001

J. Biol. Chem., Vol. 276, Issue 19, 15990-15995, May 11, 2001
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ATP-bound Topoisomerase II as a Target for Antitumor Drugs*

Huimin WangDagger , Yong MaoDagger , Nai ZhouDagger , Tao Hu§, Tao-Shih Hsieh§, and Leroy F. LiuDagger

From the Dagger  Department of Pharmacology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, Piscataway, New Jersey 08854 and the § Department of Biochemistry, Duke University Medical School, Durham, North Carolina 27710

Topoisomerase II (TOP2) poisons interfere with the breakage/reunion reaction of TOP2 resulting in DNA cleavage. In the current studies, we show that two different classes (ATP-sensitive and -insensitive) of TOP2 poisons can be identified based on their differential sensitivity to the ATP-bound conformation of TOP2. First, in the presence of 1 mM ATP or the nonhydrolyzable analog adenosine 5'-(beta ,gamma -imino)triphosphate, TOP2-mediated DNA cleavage induced by ATP-sensitive TOP2 poisons (e.g. doxorubicin, etoposide, mitoxantrone, and 4'-(9-acridinylamino)methanesulfon-m-anisidide) was 30-100-fold stimulated, whereas DNA cleavage induced by ATP-insensitive TOP2 poisons (e.g. amonafide, batracylin, and menadione) was only slightly (less than 3-fold) affected. In addition, ADP was shown to strongly antagonize TOP2-mediated DNA cleavage induced by ATP-sensitive but not ATP-insensitive TOP2 poisons. Second, C427A mutant human TOP2alpha , which exhibits reduced ATPase activity, was shown to exhibit cross-resistance to all ATP-sensitive but not ATP-insensitive TOP2 poisons. Third, using ciprofloxacin competition assay, TOP2-mediated DNA cleavage induced by ATP-sensitive but not ATP-insensitive poisons was shown to be antagonized by ciprofloxacin. These results suggest that ATP-bound TOP2 may be the specific target of ATP-sensitive TOP2 poisons. Using Lac repressor-operator complexes as roadblocks, we show that ATP-bound TOP2 acts as a circular clamp capable of entering DNA ends and sliding on unobstructed duplex DNA.

* This work was supported by National Institutes of Health Grants GM27731 and CA39662 (to L. F. L.) and GM29006 (to T. S. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pharmacology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854. Tel.: 732-235-4592; Fax: 732-235-4073; E-mail: lliu@umdnj.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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