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Molecular and Cellular Biology, May 2006, p. 3414-3431, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3414-3431.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Protein Kinase C Activates Topoisomerase II To Induce Apoptotic Cell Death in Response to DNA Damage

Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan,¹ Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan²

Received 17 January 2006/ Accepted 3 February 2006

DNA topoisomerase II is an essential nuclear enzyme that modulates DNA processes by altering the topological state of double-stranded DNA. This enzyme is required for chromosome condensation and segregation; however, the regulatory mechanism of its activation is largely unknown. Here we demonstrate that topoisomerase II is activated in response to genotoxic stress. Concomitant with the activation, the expression of topoisomerase II is increased following DNA damage. The results also demonstrate that the proapoptotic kinase protein kinase C (PKC) interacts with topoisomerase II. This association is in an S-phase-specific manner and is required for stabilization and catalytic activation of topoisomerase II in response to DNA damage. Conversely, inhibition of PKC activity attenuates DNA damage-induced activation of topoisomerase II. Finally, aberrant activation of topoisomerase II by PKC is associated with induction of apoptosis upon exposure to genotoxic agents. These findings indicate that PKC regulates topoisomerase II and thereby cell fate in the genotoxic stress response.

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