Fe65 is required for Tip60-directed histone H4 acetylation at DNA strand breaks.
Fe65 is a binding partner of the Alzheimer's beta-amyloid precursor protein APP. The possible involvement of this protein in the cellular response to DNA damage was suggested by the observation that Fe65 null mice are more sensitive to genotoxic stress than WT counterpart. Fe65 associated with chromatin under basal conditions and its involvement in DNA damage repair requires this association. A known partner of Fe65 is the histone acetyltransferase Tip60. Considering the crucial role of Tip60 in DNA repair, we explored the hypothesis that the phenotype of Fe65 null cells depended on its interaction with Tip60. We demonstrated that Fe65 knockdown impaired recruitment of Tip60-TRRAP complex to DNA double strand breaks and decreased histone H4 acetylation. Accordingly, the efficiency of DNA repair was decreased upon Fe65 suppression. To explore whether APP has a role in this mechanism, we analyzed a Fe65 mutant unable to bind to APP. This mutant failed to rescue the phenotypes of Fe65 null cells; furthermore, APP/APLP2 suppression results in the impairment of recruitment of Tip60-TRRAP complex to DNA double strand breaks, decreased histone H4 acetylation and repair efficiency. On these bases, we propose that Fe65 and its interaction with APP play an important role in the response to DNA damage by assisting the recruitment of Tip60-TRRAP to DNA damage sites.
Stante
Maria
M
CEINGE Centro d'Ingegneria Genetica Biotecnologie Avanzate, European School of Molecular Medicine, and Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, I-80145 Napoli, Italy.
Minopoli
Giuseppina
G
Passaro
Fabiana
F
Raia
Maddalena
M
Vecchio
Luigi Del
LD
Russo
Tommaso
T
D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D053960:DNA Breaks; D004260:DNA Repair; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D058255:Protease Nexins; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000378:metabolism; D015534:Trans-Activators
D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C486243:Apbb1 protein, mouse; D006657:Histones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D015534:Trans-Activators; C113829:transformation-transcription domain-associated protein; D051548:Histone Acetyltransferases; C523065:Kat5 protein, mouse; D000074443:Lysine Acetyltransferase 5