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.