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A Precise Interchromosomal Reciprocal Exchange between Hot Spots for Cleavable Complex Formation by Topoisomerase II in Amsacrine-treated Chinese Hamster Ovary Cells¹

Departments of Pharmacology and Toxicology [R-H. Z., P. W., L. F. P.] and Human Genetics [Y. Z., C. K. J-C.], Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298

Among the aprt mutations induced in confluence-arrested Chinese hamster ovary D422 cells by the topoisomerase II poison amsacrine, there was a reciprocal exchange between the aprt gene and an unrelated sequence, accompanied by a chromosomal translocation at the aprt locus. The breakpoints in both parental sequences were hot spots for amsacrine-stimulated DNA cleavage in vitro, and the novel junctions formed were precisely as expected for a mechanism involving reciprocal exchange of topoisomerase II subunits followed by resealing of the breaks and correction of mismatches in the cohesive ends. The results are consistent with a role for direct subunit exchange in the production of chromosomal translocations by topoisomerase poisons, although more complex models involving double-strand breakage and repair could produce reciprocal exchanges of similar specificity.

¹ Supported by NIH Grants CA40615 and HD33527 from the United States Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, 410 North 12th Street, P.O. Box 980613, Richmond, VA 23298. Phone: (804) 828-9640; E-mail: LPOVIRK@gems.vcu.edu.

Received 7/25/97. Accepted 9/22/97.

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