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J Biol Chem, Vol. 273, Issue 50, 33660-33666, December 11, 1998

Essential Mitotic Functions of DNA Topoisomerase II Are Not Adopted by Topoisomerase II in Human H69 Cells

Pernille Grue, Alexander Gräßer, Maxwell Sehested^§, Peter B. Jensen^§, Annette Uhse, Tobias Straub, Winfried Ness^¶, and Fritz Boege

From the  Medizinische Poliklinik, University of Würzburg, Klinikstraße 6-8, D-97070 Würzburg, Germany, the ^§ Department of Pathology and Finsen Center, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark, and the ^¶ Institute of Anatomy, University of Würzburg, D-97070 Würzburg, Germany

Unique functions of mammalian DNA-topoisomerases II and - are suggested by their distinct cellular distribution and chromatin binding at mitosis. Here, we studied H69-VP cells that, due to a homozygous mutation, express topoisomerase II mostly outside the nucleus. In these cells topoisomerase II showed a normal nuclear localization. However, at mitosis it diffused away from the chromatin despite the nuclear lack of the -isoform. 80% of these cells performed chromosome condensation and disjunction with the aid of cytosolic topoisomerase II, which bound to the mitotic chromatin with low affinity. However, the genotype of these cells was highly polyploid indicating an increased rate of non-disjunction. In 20% of the mutant cells neither topoisomerase II isoform was bound to the mitotic chromatin, which appeared as an unstructured DNA spheroid unable to undergo disjunction and cytokinesis. Parental H69 cells expressing topoisomerase II inside the nucleus exhibited high affinity binding of the enzyme to the mitotic chromatin. Their genotype was mostly diploid and stable. We conclude (i) that high affinity chromatin binding of topoisomerase II is essential for chromosome condensation/disjunction and (ii) that topoisomerase II does not adopt these functions.

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