The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage

Francesco Cecconi (1) , Daniela de Zio (1) , Matteo Bordi (1) , Elisa Tino (1) , Chiara Lanzuolo (1) , Eugenio Mora (1) , Fabiola Ciccosanti (1) , Gian Maria Fimia (1) , Valerio Orlando (1) , Elisabetta Ferraro (1)

1 Dulbecco Telethon Institute/Department of Biology

Apaf1 is a key regulator of the mitochondrial intrinsic pathway of apoptosis, since it activates executioner caspases by forming the apoptotic machinery apoptosome. Its genetic regulation and its post-translational modification are crucial under the various conditions where apoptosis occurs. Here we describe Ku70/86, a mediator of non-homologous end-joining pathway of DNA repair, as a novel regulator of Apaf1 transcription. Through analysing different Apaf1 promoter mutants, we identified an element repressing the Apaf1 promoter. We demonstrated that Ku70/86 is a nuclear factor able to bind this repressing element and down-regulating Apaf1 transcription. We also found that Ku70/86 interaction with Apaf1 promoter is dynamically modulated upon DNA damage. The effect of this binding is a down-regulation of Apaf1 expression immediately following the damage to DNA; conversely, we observed Apaf1 up-regulation and apoptosis activation when Ku70/86 unleashes the Apaf1-repressing element. Therefore, besides regulating DNA repair, our results suggest that Ku70/86 binds to the Apaf1 promoter and represses its activity. This may help to inhibit the apoptosome pathway of cell death and contribute to regulate cell survival

Mots clés: Apoptosis; apoptosome; transcriptional regulation

Francesco Cecconi, Daniela de Zio, Matteo Bordi, Elisa Tino, Chiara Lanzuolo, et al.. The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.125⟩. ⟨hal-00587968⟩