title: HDAC5, a key component in temporal regulation of p53-mediated transactivation in response to genotoxic stress.
abstract: Despite being one of the most well-studied transcription factors, the temporal regulation of p53-mediated transcription is not very well understood. Recent data suggest that target specificity of p53-mediated transactivation is achieved by posttranslational modifications of p53. K120 acetylation is a modification critical for recruitment of p53 to proapoptotic targets. Our data reveal that histone deacetylase 5 (HDAC5) binds to p53 and abrogates K120 acetylation, resulting in preferential recruitment of p53 to proarrest and antioxidant targets at early phases of stress. However, upon prolonged genotoxic stress, HDAC5 undergoes nuclear export. Concomitantly, p53 is acetylated at the K120 residue and selectively transactivates proapoptotic target genes, leading to onset of apoptosis. Furthermore, upon genotoxic stress in mice where HDAC5 expression is downregulated, the onset of apoptosis is accelerated in the highly vulnerable tissues. These findings suggest that HDAC5 is a key determinant of p53-mediated cell fate decisions in response to genotoxic stress.
authors.affiliation: Molecular Oncology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Nirmalya
authors.initials: N
authors.lastname: Sen
authors.forename: Rajni
authors.initials: R
authors.lastname: Kumari
authors.forename: Manika Indrajit
authors.initials: MI
authors.lastname: Singh
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Das
mesh_terms: D000107:Acetylation / Q000187:drug effects*; D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000256:Adenoviridae / Q000378:metabolism / Q000472:pathogenicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D005047:Etoposide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D045325:HCT116 Cells; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D017382:Reactive Oxygen Species / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; C404500:HDAC5 protein, human; D006655:Histone Deacetylases; D008239:Lysine