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Sykes SM , Stanek TJ , Frank A , Murphy ME , McMahon SB
Acetylation of the DNA binding domain regulates transcription-independent apoptosis by p53
J Biol Chem. 2009 Jul 24;284(30) :20197-205
PMID: 19494119    PMCID: PMC2740446    URL: https://www.ncbi.nlm.nih.gov/pubmed/19494119
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The tumor suppressor p53 induces apoptosis by altering the transcription of pro-apoptotic targets in the nucleus and by a direct, nontranscriptional role at the mitochondria. Although the post-translational modifications regulating nuclear apoptotic functions of p53 have been thoroughly characterized, little is known of how transcription-independent functions are controlled. We and others identified acetylation of the p53 DNA binding domain at lysine 120 as a critical event in apoptosis induction. Although initial studies showed that Lys-120 acetylation plays a role in p53 function in the nucleus, we report here a role for Lys-120 acetylation in transcription-independent apoptosis. We demonstrate that the Lys-120-acetylated isoform of p53 is enriched at mitochondria. The acetylation of Lys-120 does not appear to regulate the ability of p53 to interact with the pro-apoptotic proteins BCL-XL and BAK. However, displacement of the inhibitory MCL-1 protein from BAK is compromised when Lys-120 acetylation is blocked. Functional studies show that mutation of Lys-120 to a nonacetylated residue, as occurs in human cancer, inhibits transcription-independent apoptosis, and enforced acetylation of Lys-120 enhances transcription-independent apoptosis. These data support a model whereby Lys-120 acetylation contributes to both the transcription-dependent and -independent apoptotic pathways induced by p53.
Sykes, Stephen M Stanek, Timothy J Frank, Amanda Murphy, Maureen E McMahon, Steven B eng CA090465/CA/NCI NIH HHS/ R01 CA102184/CA/NCI NIH HHS/ R01 CA098172/CA/NCI NIH HHS/ R01 CA090465/CA/NCI NIH HHS/ CA098172/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't J Biol Chem. 2009 Jul 24;284(30):20197-205. doi: 10.1074/jbc.M109.026096. Epub 2009 Jun 3.