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J. Biol. Chem., Vol. 279, Issue 29, 30830-30835, July 16, 2004

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Specific Role for p300/CREB-binding Protein-associated Factor Activity in E2F1 Stabilization in Response to DNA Damage^*

Alessandra Ianari, Rita Gallo¶||, Marzia Palma, Edoardo Alesse¶, and Alberto Gulino**

From the Department of Experimental Medicine and Pathology, University of Rome "La Sapienza," 00161 Rome, Italy, ^¶Department of Experimental Medicine, University of L'Aquila, 67100 L'Aquila, Italy, and ^**Neuromed Institute, 86077 Pozzilli, Italy

E2F1, a member of the E2F family of transcription factors, plays a pivotal role in controlling both physiological cell-cycle progression and apoptotic cell death in response to DNA damage and oncogene activation. In response to genotoxic stresses, E2F1 is stabilized by signals that include ATM-dependent phosphorylation. We recently demonstrated that DNA damage induces also E2F1 acetylation, which is required for its recruitment onto apoptotic gene promoters. Here we show that E2F1 is stabilized in response to doxorubicin and cisplatin treatments even in the absence of either ATM-dependent phosphorylation or p53 and cAbl, two major transducers of DNA damage signaling. We found that acetylation of E2F1 is, instead, required to stabilize the protein in response to doxorubicin. Finally, we report that the formation of E2F1-p300/CREB-binding protein-associated factor (P/CAF) complexes is preferentially induced in doxorubicin-treated cells, and that P/CAF acetyltransferase (HAT), but not p300 HAT activity, is required for a significant E2F1 stabilization and accumulation. Our results unveil a differential role of P/CAF and p300 in acetylation-induced stabilization of E2F1, thus supporting a specific role for P/CAF HAT activity in E2F1-dependent apoptosis in response to DNA damage.

Received for publication, March 3, 2004 , and in revised form, April 21, 2004.

^* This work was partially supported by grants from the Ministry of Health, the Associazione Italiana per la Ricerca sul Cancro, the Ministry of University and Research, the National Research Council, and Center of Excellence BEMM. 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.

Supported by a fellowship from the American Italian Cancer Foundation.

^|| Supported by a fellowship from Fondazione Italiana per la Ricerca sul Cancro.

To whom correspondence should be addressed. Tel.: 00390-6495-8637; Fax: 00390-6446-1974; E-mail: Alberto.gulino{at}uniroma1.it.

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