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J. Biol. Chem., Vol. 279, Issue 46, 48013-48023, November 12, 2004

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The Transcriptional Repressor hDaxx Potentiates p53-dependent Apoptosis^*

Monica Gostissa, Manuela Morelli, Fiamma Mantovani, Elisa Guida, Silvano Piazza, Licio Collavin, Claudio Brancolini¶, Claudio Schneider¶, and Giannino Del Sal||**

From the Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, 34012, Trieste, Italy, Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole and ^||Centro di Eccellenza di Biocristallografia, Università di Trieste, via Licio Giorgeri 1, 34100, Trieste, Italy, and ^¶Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Piazzale Kolbe 4, 33100, Udine, Italy

p53 and its homologues p73 and p63 are transcription factors that play an essential role in modulating cell cycle arrest and cell death in response to several environmental stresses. The type and intensity of these responses, which can be different depending on the inducing stimulus and on the overall cellular context, are believed to rely on the activation of defined subsets of target genes. The proper activation of p53 family members requires the coordinated action of post-translational modifications and interaction with several cofactors. In this study, we demonstrate that the multifunctional protein hDaxx interacts with p53 and its homologues, both in vitro and in vivo, and modulates their transcriptional activity. Moreover, we show that hDaxx, which has been implicated in several apoptotic pathways, increases the sensitivity to DNA damage-induced cell death and that this effect requires the presence of p53. Although hDaxx represses p53-dependent transcription of the p21 gene, it does not affect the activation of proapoptotic genes, and therefore acts by influencing the balance between cell cycle arrest and proapoptotic p53 targets. Our results therefore underline the central role of hDaxx in modulating the apoptotic threshold upon several stimuli and identify it as a possible integrating factor that coordinates the response of p53 family members.

Received for publication, October 1, 2003 , and in revised form, August 10, 2004.

^* This work was supported in part by grants from the Associazione Italiana per la Ricerca sul Cancro, Consiglio Nazionale delle Ricerche, and Telethon (to G. D. S.). 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.

^** To whom correspondence should be addressed. Tel.: 39-040398992; Fax: 39-040398990; E-mail: delsal{at}area.trieste.it.

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