E2F3A is a mediator of the cellular response to DNA damage.

LB-45 In response to DNA damage, cells may either undergo cell cycle arrest or apoptosis. This cell fate decision involves the activation of a transcriptional program that will determine the proper response to the genotoxic stress incurred. The E2F1 transcription factor has emerged as a critical apoptotic effector of the DNA damage response. E2F1 is induced by DNA damaging agents and it is required for the induction of apoptosis by genotoxic stress. We demonstrate that the E2F family member, E2F3a, is also induced by DNA damage. Treatment with different DNA damaging agents at doses that induce apoptosis results in the induction of E2F3a. In contrast, the E2F3 isoform, E2F3b, is downregulated in response to genotoxic stress. We demonstrate that the induction of E2F3a occurs soon after treatment with DNA damaging agents. Additionally, we find that E2F3a has a longer half-life in cells treated with chemotherapy, suggesting that the upregulation of E2F3a occurs through post-translational mechanisms. We provide two lines of evidence that suggest a role for the checkpoint kinases in the induction of E2F3a. First, siRNA knockdown of chk1 blocks the accumulation of E2F3 in chemotherapy treated cells. Second, mutation of a putative chk1 site in E2F3a eliminates the DNA damage inducibility of the mutant protein. We further demonstrate that E2F3a is required for chemotherapy induced apoptosis since E2F3a knockdown protects cells from cell death induced by different DNA damaging agents. Moreover, we find that some chemotherapeutic agents transcriptionally induce E2F1 in an E2F3a dependent manner. Furthermore, we demonstrate that in the absence of E2F3a, E2F1 mRNA and protein are poorly induced by DNA damage. Moreover, p73, a pro-apoptotic E2F target gene, is not transcriptionally activated in drug treated cells that are deficient for E2F3a. Our data challenges the conventional view that E2F1 is the sole “activator” E2F that is induced by DNA damage. Thus, we propose that a novel function of E2F3a is to coordinate the transcriptional activation of pro-apoptotic genes in response to DNA damage.