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J. Biol. Chem., Vol. 282, Issue 2, 831-835, January 12, 2007

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Essential Roles for Fe65, Alzheimer Amyloid Precursor-binding Protein, in the Cellular Response to DNA Damage^*

Giuseppina Minopoli¹, Maria Stante¹², Francesco Napolitano, Francesca Telese, Luigi Aloia², Mario De Felice^¶, Roberto Di Lauro^¶, Roberto Pacelli^||, Arturo Brunetti^||, Nicola Zambrano, and Tommaso Russo³

From the CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy, the Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, 80131 Napoli, Italy, ^¶BioGeM Scarl-CEINGE, 80145 Napoli, Italy, and the ^||Istituto di Biostrutture e Bioimmagini, CNR, Dipartimento di Diagnostica per Immagini e Radioterapia, Universitàdi Napoli Federico II, 80131 Napoli, Italy

Fe65 interacts with the cytosolic domain of the Alzheimer amyloid precursor protein (APP). The functions of the Fe65 are still unknown. To address this point we generated Fe65 knockout (KO) mice. These mice do not show any obvious phenotype; however, when fibroblasts (mouse embryonic fibroblasts), isolated from Fe65 KO embryos, were exposed to low doses of DNA damaging agents, such as etoposide or H₂O₂, an increased sensitivity to genotoxic stress, compared with wild type animals, clearly emerged. Accordingly, brain extracts from Fe65 KO mice, exposed to non-lethal doses of ionizing radiations, showed high levels of -H2AX and p53, thus demonstrating a higher sensitivity to X-rays than wild type mice. Nuclear Fe65 is necessary to rescue the observed phenotype, and few minutes after the exposure of MEFs to DNA damaging agents, Fe65 undergoes phosphorylation in the nucleus. With a similar timing, the proteolytic processing of APP is rapidly affected by the genotoxic stress: in fact, the cleavage of the APP COOH-terminal fragments by -secretase is induced soon after the exposure of cells to etoposide, in a Fe65-dependent manner. These results demonstrate that Fe65 plays an essential role in the response of the cells to DNA damage.

Received for publication, October 23, 2006 , and in revised form, November 17, 2006.

^* This work was supported by grants from the Alzheimer Association, VI Framework Programme of the European Community (APOPIS), and PRIN2005 (to T. R.) and from PRIN2005 (to N. Z.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material (parts 1 and 2).

¹ These authors contributed equally to this paper.

² These two authors are Ph.D. students of the SEMM, European School of Molecular Medicine.

³ To whom correspondence should be addressed: CEINGE Biotecnologie Avanzate, via Comunale Margherita 482, 80145 Napoli, Italy. Tel.: 39-0813737863; E-mail: russot{at}dbbm.unina.it.

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