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Conjugation of Human Topoisomerase 2 with Small Ubiquitin-like Modifiers 2/3 in Response to Topoisomerase Inhibitors: Cell Cycle Stage and Chromosome Domain Specificity

¹ Instituto de Medicina Molecular, Faculdade de Medicina, Lisboa, Portugal; ² Departmento de Morfologia e Função, CIISA, Faculdade de Medicina Veterinaria, Lisboa, Portugal and ³ Center for Interdisciplinary Research, School of Life Science, University of Dundee, Scotland, United Kingdom

Requests for reprints: João Ferreira, Instituto de Medicina Molecular/IMM, Faculdade de Medicina, Edificio Egas Moniz, piso 3A-sala 5, Av. Professor Egas Moniz, 1649-028 Lisboa, Portugal. Phone: 00351-21-7999-519. E-mail: hjoao{at}fm.ul.pt.

Key Words: topoisomerase • SUMO • chromosomes • cell cycle • inhibitors

Type 2 topoisomerases, in particular the isoform in human cells, play a key role in cohesion and sister chromatid separation during mitosis. These enzymes are thus vital for cycling cells and are obvious targets in cancer chemotherapy. Evidence obtained in yeast and Xenopus model systems indicates that conjugation of topoisomerase 2 with small ubiquitin-like modifier (SUMO) proteins is required for its mitotic functions. Here, we provide biochemical and cytologic evidence that topoisomerase 2 is conjugated to SUMO-2/3 during interphase and mitosis in response to topoisomerase 2 inhibitors and "poisons" (ICRF-187, etoposide, doxorubicin) that stabilize catalytic intermediates (cleavage complexes, closed clamp forms) of the enzyme onto target DNA. During mitosis, SUMO-2/3–modified forms of topoisomerase 2 localize to centromeres and chromosome cores/axes. However, centromeres are unresponsive to inhibitors during interphase. Furthermore, formation of topoisomerase 2–SUMO-2/3 conjugates within mitotic chromosomes strongly correlates with incomplete chromatid decatenation and decreases progressively as cells approach the metaphase-anaphase transition. We also found that the PIASy protein, an E3 ligase for SUMO proteins, colocalizes with SUMO-2/3 at the mitotic chromosomal cores/axes and is necessary for both formation of SUMO-2/3 conjugates and proper chromatid segregation. We suggest that the efficacy of topoisomerase inhibitors to arrest cells traversing mitosis may relate to their targeting of topoisomerase 2–SUMO-2/3 conjugates that concentrate at mitotic chromosome axes and are directly involved in chromatid arm separation. [Cancer Res 2008;68(7):2409–18]

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				Correction: Human Topoisomerase 2{alpha} Conjugates with SUMO-2 Cancer Res., April 15, 2008; 68(8): 3076 - 3076. [Full Text] [PDF]