Cell cycle remodeling is sufficient to repress apoptosis. Suozhi Qi, Christiane Hassel, Brian R. Calvi. Indiana University, Bloomington, IN.

   Severe DNA damage usually triggers eukaryotic cells to undergo a programmed cell death called apoptosis. However, we have found that when cells are in the endocycle, which is characterized by alternating G and S phase, they do not apoptose in response to DNA damage. We are investigating how cell cycle remodeling modulates the apoptotic response. To do this, we are altering the cell cycle through RNAi knockdown of crucial cell cycle regulators and testing the apoptotic responses to DNA damage caused by irradiation. Knocking down Cyclin A or overexpressing Fizzy-related, a subunit of anaphase promoting complex, switches normal mitotic cells into the endocycle and inhibits apoptosis after irradiation. We have also found that arresting the cell cycle by knocking down Cdk1 or Cyclin E blocks the apoptotic responses in Drosophila. Our data indicate that cell cycle remodeling is sufficient to block apoptosis independent of other developmental inputs. These unexpected findings have important implications for understanding how polyploid tumor cells escape apoptosis and contribute to disease progression.