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J. Biol. Chem., Vol. 282, Issue 12, 8812-8820, March 23, 2007

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An Essential Role of Human Ada3 in p53 Acetylation^*

Alo Nag, Aleksandra Germaniuk-Kurowska, Manjari Dimri^¶, Michael A. Sassack, Channabasavaiah Basavaraju Gurumurthy, Qingshen Gao, Goberdhan Dimri, Hamid Band^¶||1, and Vimla Band^||2

From the Divisions of Cancer Biology and ^¶Molecular Oncology, Evanston Northwestern Healthcare Research Institute, the Department of Medicine, Feinberg School of Medicine, and the ^||Department of Biochemistry, Molecular Biology and Cell Biology, Weinberg College of Arts, Northwestern University, Evanston, Illinois 60201

The p53 tumor suppressor protein functions as a critical component of genotoxic stress response by regulating the expression of effector gene products that control the fate of a cell following DNA damage. Unstressed cells maintain p53 at low levels through regulated degradation, and p53 levels and activity are rapidly elevated upon genotoxic stress. Biochemical mechanisms that control the levels and activity of p53 are therefore of great interest. We and others have recently identified hAda3 (human homologue of yeast alteration/deficiency in activation 3) as a p53-interacting protein and enhancer of p53 activity. Here, we show that endogenous levels of p53 and Ada3 interact with each other, and by using inducible overexpression and short hairpin RNA-mediated knockdown strategies we demonstrate that hAda3 stabilizes p53 protein by promoting its acetylation. Use of a p53 mutant with mutations of known p300/CREB-binding protein acetylation sites demonstrated that hAda3-dependent acetylation is required for increase in p53 stability and target gene induction. Importantly, we demonstrate that endogenous hAda3 is essential for DNA damage-induced acetylation and stabilization of p53 as well as p53 target gene induction. Overall, our results establish hAda3, a component of coactivator complexes that include histone acetyltransferase p300/CREB-binding protein, as a critical mediator of acetylation-dependent stabilization and activation of p53 upon genotoxic stress in mammalian cells.

Received for publication, November 9, 2006 , and in revised form, January 29, 2007.

^* This work was supported by National Institutes of Health Grants CA94143, CA96844, and CA81076 (to V. B.) and CA87986, CA76118, CA99900, and CA99163 (to H. B.). 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.

¹ Holder of the Jean Ruggles-Romoser Chair for Cancer Research.

² Supported by the Duckworth family through the Duckworth Family Chair for Breast Cancer Research. To whom correspondence should be addressed: Division of Cancer Biology, ENH Research Institute, 1001 University Pl., Evanston, IL 60201. Tel.: 224-364-7501; Fax: 224-364-7402; E-mail: v-band{at}northwestern.edu.

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