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The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage (Articolo in rivista)

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The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage (Articolo in rivista) (literal)

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De Zio D. 1,2, Bordi M. 1,2, Tino E.2, Lanzuolo C.3,4, Ferraro E.2, Mora E.2, Ciccosanti F.5, Fimia G.M.5, Orlando V.3, Cecconi F.1,2. (2011)
The DNA repair complex Ku70/86 modulates Apaf1 expression upon DNA damage
in Cell death and differentiation
(literal)

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De Zio D. 1,2, Bordi M. 1,2, Tino E.2, Lanzuolo C.3,4, Ferraro E.2, Mora E.2, Ciccosanti F.5, Fimia G.M.5, Orlando V.3, Cecconi F.1,2. (literal)

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2010 Oct 22. [Epub ahead of print]- (March 2011) | doi:10.1038/cdd.2010.125 (literal)

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1) - Department of Biology, Dulbecco Telethon Institute, University of Rome Tor Vergata, 00133 Rome, Italy; 2) -Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; 3) - Dulbecco Telethon Institute at the IRCCS Fondazione Santa Lucia and EBRI, 00143 Rome, Italy; 4) - CNR Institute of Neurobiology and Molecular Medicine, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy; 5) National Institute for Infectious Diseases, Lazzaro Spallanzani, 00149 Rome, Italy (literal)

Titolo

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

Abstract

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. (literal)

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