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J. Biol. Chem., Vol. 281, Issue 4, 2347-2357, January 27, 2006

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DNA Damage Promotes Histone Deacetylase 4 Nuclear Localization and Repression of G₂/M Promoters, via p53 C-terminal Lysines^*

Valentina Basile, Roberto Mantovani1, and Carol Imbriano, Recipient of a Fondazione Italiana per la Ricerca sul Cancro fellowship2

From the Dipartimento di Biologia Animale, Università di Modena e Reggio, Via Campi 213/d, 41100 Modena, Italy and Dipartimento di Scienze Biomolecolari e Biotecnologie, Università di Milano, Via Celoria 26, 20133 Milano, Italy

Repression of G₂/M promoters after DNA damage is an active mechanism that requires the p53 tumor suppressor. We have recently found that histone deacetylase 4 (HDAC4) is recruited on NF-Y-dependent repressed promoters. In this report, we describe the relationship between p53 and HDAC4 recruitment following DNA damage using immunofluorescence, chromatin immunoprecipitation, and transfection experiments. HDAC4 shuttles from the cytoplasm into the nucleus, following DNA damage, independently of the activation of p53 and becomes associated with promoters through a p53-dependent mechanism. The C-terminal lysines of p53, which are acetylated and methylated, are required for HDAC4 recruitment and transcriptional repression. Trichostatin treatment, but not HDAC4 functional inactivation, relieves the adriamycin-mediated repression of G₂/M promoters. Our results indicate that HDAC4 is a component of the DNA damage response and that post-translational modifications of p53 are important for repression of G₂/M genes.

Received for publication, July 15, 2005 , and in revised form, November 14, 2005.

^* 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 Fig. 5.

¹ Supported by grants from Associazone Italiana per la Ricerca sul Cancro and by PRIN-MIUR.

² To whom correspondence should be addressed: Dipartimento di Biologia Animale, Università di Modena e Reggio Emilia, Via Campi 213/d, 41100 Modena, Italy. Tel.: 39-059-2055542; Fax: 39-059-2055548; E-mail: cimbriano{at}unimo.it.

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