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Originally published In Press as doi:10.1074/jbc.M104009200 on August 23, 2001

J. Biol. Chem., Vol. 276, Issue 44, 40652-40658, November 2, 2001
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26 S Proteasome-mediated Degradation of Topoisomerase II Cleavable Complexes*

Yong Mao, Shyamal D. Desai, Chun-Yuan TingDagger , Jaulang HwangDagger , and Leroy F. Liu§

From the Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635 and the Dagger  Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan

DNA topoisomerase II (TOP2) cleavable complexes represent an unusual type of DNA damage characterized by reversible TOP2-DNA cross-links and DNA double strand breaks. Many antitumor drugs and physiological stresses are known to induce TOP2 cleavable complexes leading to apoptotic cell death and genomic instability. However, the molecular mechanism(s) for repair of TOP2 cleavable complexes remains unclear. In the current studies, we show that TOP2 cleavable complexes induced by the prototypic TOP2 poison VM-26 are proteolytically degraded by the ubiquitin/26 S proteasome pathway. Surprisingly the TOP2beta isozyme is preferentially degraded over TOP2alpha isozyme. In addition, transcription inhibitors such as 5,6-dichlorobenzimidazole riboside and camptothecin can substantially block VM-26-induced TOP2beta degradation. These results are consistent with a model in which the repair of TOP2beta cleavable complexes may involve transcription-dependent proteolysis of TOP2beta to reveal the protein-concealed double strand breaks.

* This work was supported by National Institutes of Health Grants GM27731 and CA 39662, Grant NSC 89-2320-B001-075 from the National Science Council of Taiwan, and Academia Sinica.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, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Ln., Piscataway, NJ 08854. Tel.: 732-235-4912; 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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