Protein kinase C δ activates topoisomerase IIα to induce apoptotic cell death in response to DNA damage

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 Hot is activated in response to genotoxic stress. Concomitant with the activation, the expression of topoisomerase Hot is increased following DNA damage. The results also demonstrate that the proapoptotic kinase protein kinase C delta (PKC delta) interacts with topoisomerase Hot. This association is in an S-phase-specific manner and is required for stabilization and catalytic activation of topoisomerase Hot in response to DNA damage. Conversely, inhibition of PKC delta activity attenuates DNA damage-induced activation of topoisomerase Ha. Finally, aberrant activation of topoisomerase Hot by PKC delta is associated with induction of apoptosis upon exposure to genotoxic agents. These findings indicate that PKC delta regulates topoisomerase Hot and thereby cell fate in the genotoxic stress response.