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Originally published In Press as doi:10.1074/jbc.M102674200 on May 15, 2001

J. Biol. Chem., Vol. 276, Issue 28, 26708-26714, July 13, 2001
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Overexpression of Type I Topoisomerases Sensitizes Yeast Cells to DNA Damage*

John L. NitissDagger , Karin C. Nitiss, Angela Rose, and Jessica L. Waltman

From the Molecular Pharmacology Department, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

DNA topoisomerases play essential roles in many DNA metabolic processes. It has been suggested that topoisomerases play an essential role in DNA repair. Topoisomerases can introduce DNA damage upon exposure to drugs that stabilize the covalent protein-DNA intermediate of the topoisomerase reaction. Lesions in DNA are also able to trap topoisomerase-DNA intermediates, suggesting that topoisomerases have the potential to either assist in DNA repair by locating sites of damage or exacerbating DNA damage by generation of additional damage at the site of a lesion. We have shown that overexpression of yeast topoisomerase I (TOP1) conferred hypersensitivity to methyl methanesulfonate and other DNA-damaging agents, whereas expression of a catalytically inactive enzyme did not. Overexpression of topoisomerase II did not change the sensitivity of cells to these DNA-damaging agents. Yeast cells lacking TOP1 were not more resistant to DNA damage than cells expressing wild type levels of the enzyme. Yeast topoisomerase I covalent complexes can be trapped efficiently on UV-damaged DNA. We suggest that TOP1 does not participate in the repair of DNA damage in yeast cells. However, the enzyme has the potential of exacerbating DNA damage by forming covalent DNA-protein complexes at sites of DNA damage.

* This work was supported by National Institutes of Health Grant CA52814 (NCI), Core Grant CA21765, and by the American Lebanese Syrian Associated Charities (ALSAC).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.

Dagger To whom correspondence should be addressed: Molecular Pharmacology Department, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis TN 38105. Tel.: 901-495-2794; Fax: 901-521-1668; E-mail: john.nitiss@stjude.org.

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