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Molecular and Cellular Biology, May 2005, p. 3737-3751, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3737-3751.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Direct p53 Transcriptional Repression: In Vivo Analysis of CCAAT-Containing G2/M Promoters

Carol Imbriano,1 Aymone Gurtner,2 Fabienne Cocchiarella,1 Silvia Di Agostino,2 Valentina Basile,1 Monica Gostissa,3 Matthias Dobbelstein,4 Giannino Del Sal,3,5 Giulia Piaggio,2 and Roberto Mantovani6*

Dipartimento di Biologia Animale, Universita di Modena e Reggio, Modena,1 Dipartimento di Oncologia Sperimentale, Istituto Regina Elena, Rome,2 Dipartimento di Biochimica, Biofisica, a Chimica delle Macromolecole, Universita di Trieste,3 Laboratorio Nazionale CIB, Trieste,5 Dipartimento di Scienze Biomolecolare e Biotecnologie, Universita di Milano, Milan, Italy,6 Medical Biotechnology Center, Institute of Medical Biology, Odense, Denmark4

Received 30 June 2004/ Returned for modification 14 October 2004/ Accepted 20 January 2005

In response to DNA damage, p53 activates G1/S blocking and apoptotic genes through sequence-specific binding. p53 also represses genes with no target site, such as those for Cdc2 and cyclin B, key regulators of the G2/M transition. Like most G2/M promoters, they rely on multiple CCAAT boxes activated by NF-Y, whose binding to DNA is temporally regulated during the cell cycle. NF-Y associates with p53 in vitro and in vivo through the {alpha}C helix of NF-YC (a subunit of NF-Y) and a region close to the tetramerization domain of p53. Chromatin immunoprecipitation experiments indicated that p53 is associated with cyclin B2, CDC25C, and Cdc2 promoters in vivo before and after DNA damage, requiring DNA-bound NF-Y. Following DNA damage, p53 is rapidly acetylated at K320 and K373 to K382, histones are deacetylated, and the release of PCAF and p300 correlates with the recruitment of histone deacetylases (HDACs)—HDAC1 before HDAC4 and HDAC5—and promoter repression. HDAC recruitment requires intact NF-Y binding sites. In transfection assays, PCAF represses cyclin B2, and a nonacetylated p53 mutant shows a complete loss of repression potential, despite its abilities to bind NF-Y and to be recruited on G2/M promoters. These data (i) detail a strategy of direct p53 repression through associations with multiple NF-Y trimers that is independent of sequence-specific binding of p53 and that requires C-terminal acetylation, (ii) suggest that p53 is a DNA damage sentinel of the G2/M transition, and (iii) delineate a new role for PCAF in cell cycle control.

* Corresponding author. Mailing address: Dipartimento di Scienze Biomolecolari e Biotecnologie, Università di Milano, Via Celoria 26, 20133 Milan, Italy. Phone: 39-02-50315005. Fax: 39-02-50315044. E-mail: mantor{at}unimi.it.

Molecular and Cellular Biology, May 2005, p. 3737-3751, Vol. 25, No. 9
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.9.3737-3751.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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