p73 is a member of the p53 family often overexpressed in human cancer. Its regulation, particularly following DNA damage, is different from that of p53. Following DNA damage, we found induction of p73 at both the protein and mRNA levels. Furthermore, by using different p73 promoter fragments, we found a role for E2F1 in mediating transcription of p73. However, this observation alone does not account for the observed DNA damage-induced activation of p73 in the cells used in these experiments. By analyzing the p73 promoter sequence, we revealed a new mechanism of p73 induction associated with the removal of transcriptional repression from the p73 promoter. We found, in fact, that treatment of cells with DNA damaging agents induced nuclear export of the transcription factor C-EBPalpha and blockage of this export abolished drug-induced p73 activation. We also show that C-EBPalpha has a direct repressive activity on transfactor E2F1, and for this repression the binding of C-EBPalpha to its consensus sequence in the DNA is required. These data suggest that in normal conditions a repressor complex involving C-EBPalpha, E2F1 and perhaps other proteins is present on the p73 promoter. This repressor complex is destroyed following damage by removal of C-EBPalpha from nuclei.