c-Myc Is Necessary for DNA Damage-Induced Apoptosis in the G 2 Phase of the Cell Cycle

Abstract

ABSTRACT The c- myc proto-oncogene encodes a transcription factor that participates in the regulation of cellular proliferation, differentiation, and apoptosis. Ectopic overexpression of c-Myc has been shown to sensitize cells to apoptosis. We report here that cells lacking c-Myc activity due to disruption of the c- myc gene by targeted homologous recombination are defective in DNA damage-initiated apoptosis in the G 2 phase of the cell cycle. The downstream effector of c-Myc is cyclin A, whose ectopic expression in c- myc −/− cells rescues the apoptosis defect. The kinetics of the G 2 response indicate that the induction of cyclin A and the concomitant activation of Cdk2 represent an early step during commitment to apoptosis. In contrast, expression of cyclins E and D1 does not rescue the apoptosis defect, and apoptotic processes in G 1 phase are not affected in c- myc −/− cells. These observations link DNA damage-induced apoptosis with cell cycle progression and implicate c-Myc in the functioning of a subset of these pathways.