Open AccessThe DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage
Author(s) -
Daniela De Zio,
Matteo Bordi,
Elisa Tino,
Chiara Lanzuolo,
Elisabetta Ferraro,
Eugenio Meza Mora,
Fabiola Ciccosanti,
Gian María Fimia,
Valerio Orlando,
Francesco Cecconi
Publication year - 2010
Publication title -
cell death and differentiation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.348
H-Index - 218
eISSN - 1476-5403
pISSN - 1350-9047
DOI - 10.1038/cdd.2010.125
Subject(s) - ku70 , transcription factor , biology , dna repair , microbiology and biotechnology , dna damage , transcription (linguistics) , dna , genetics , gene , linguistics , philosophy
Apaf1 is a key regulator of the mitochondrial intrinsic pathway of apoptosis, as 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 downregulating 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 downregulation of Apaf1 expression immediately following the damage to DNA; conversely, we observed Apaf1 upregulation 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.