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Nucleic Acids Research, 2003, Vol. 31, No. 15 4373-4384
© 2003 Oxford University Press

Yeast recombination pathways triggered by topoisomerase II-mediated DNA breaks

Michelle Sabourin1, John L. Nitiss3, Karin C. Nitiss3, Kazuo Tatebayashi4, Hideo Ikeda5 and Neil Osheroff*,1,2

1 Department of Biochemistry and 2 Department of Medicine (Hematology/Oncology),Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA, 3 Department of Molecular Pharmacology, St. Jude Children’s Research Hospital, Memphis, TN 38101, USA, 4 Division of Molecular Cell Signaling, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan and 5 Institute of Medical Science, Medinet Inc., Kouhoku-ku, Yokohama 222-0033, Japan

*To whom correspondence should be addressed. Tel: +1 615 322 4338; Fax +1 615 343 1166; Email: osheron{at}ctrvax.vanderbilt.edu
Present address:
Michelle Sabourin, Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014, USA

Topoisomerase II is a ubiquitous enzyme that removes knots and tangles from the genetic material by generating transient double-strand DNA breaks. While the enzyme cannot perform its essential cellular functions without cleaving DNA, this scission activity is inherently dangerous to chromosomal integrity. In fact, etoposide and other clinically important anticancer drugs kill cells by increasing levels of topoisomerase II-mediated DNA breaks. Cells rely heavily on recombination to repair double-strand DNA breaks, but the specific pathways used to repair topoisomerase II-generated DNA damage have not been defined. Therefore, Saccharomyces cerevisiae was used as a model system to delineate the recombination pathways that repair DNA breaks generated by topoisomerase II. Yeast cells that expressed wild-type or a drug-hypersensitive mutant topoisomerase II or overexpressed the wild-type enzyme were examined. Based on cytotoxicity and recombination induced by etoposide in different repair-deficient genetic backgrounds, double-strand DNA breaks generated by topoisomerase II appear to be repaired primarily by the single-strand invasion pathway of homologous recombination. Non-homologous end joining also was triggered by etoposide treatment, but this pathway was considerably less active than single-strand invasion and did not contribute significantly to cell survival in S.cerevisiae.


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