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Originally published as Genetics Published Articles Ahead of Print on April 16, 2005.
Genetics, Vol. 170, 591-600, June 2005, Copyright © 2005
doi:10.1534/genetics.104.028795
Multiple Endonucleases Function to Repair Covalent Topoisomerase I Complexes in Saccharomyces cerevisiae
Changchun Deng, James A. Brown, Dongqing You1 and J. Martin Brown2
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305-5152
2 Corresponding author: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, CCSR South, Room 1255, 269 Campus Dr., Stanford, CA 94305-5152.
E-mail: mbrown{at}stanford.edu
Topoisomerase I plays a vital role in relieving tension on DNA strands generated during replication. However if trapped by camptothecin or other DNA damage, topoisomerase protein complexes may stall replication forks producing DNA double-strand breaks (DSBs). Previous work has demonstrated that two structure-specific nucleases, Rad1 and Mus81, protect cells from camptothecin toxicity. In this study, we used a yeast deletion pool to identify genes that are important for growth in the presence of camptothecin. In addition to genes involved in DSB repair and recombination, we identified four genes with known or implicated nuclease activity, SLX1, SLX4, SAE2, and RAD27, that were also important for protection against camptothecin. Genetic analysis revealed that the flap endonucleases Slx4 and Sae2 represent new pathways parallel to Tdp1, Rad1, and Mus81 that protect cells from camptothecin toxicity. We show further that the function of Sae2 is likely due to its interaction with the endonuclease Mre11 and that the latter acts on an independent branch to repair camptothecin-induced damage. These results suggest that Mre11 (with Sae2) and Slx4 represent two new structure-specific endonucleases that protect cells from trapped topoisomerase by removing topoisomerase-DNA adducts.
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