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

• Published in: The Journal of biological chemistry Vol. 281; no. 4; pp. 2347 - 2357
• Main Authors: Basile, Valentina, Mantovani, Roberto, Imbriano, Carol
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.01.2006; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Blotting, Western; Cell Cycle; Cell Division; Cell Nucleus - enzymology; Cell Nucleus - metabolism; Chromatin Immunoprecipitation; Cyclin B - metabolism; Cytoplasm - metabolism; DNA Damage; DNA Methylation; Doxorubicin - pharmacology; G2 Phase; Genes, p53; Histone Deacetylases - biosynthesis; Immunoprecipitation; Luciferases - metabolism; Lysine - chemistry; Mice; Microscopy, Fluorescence; NIH 3T3 Cells; Plasmids - metabolism; Protein Processing, Post-Translational; Protein Structure, Tertiary; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Transfection; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M507712200

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.