Abstract 5300: Acetylation of alteration/deficiency in activation 3 (Ada3) is essential for its stability and function

In eukaryotes histone acetylation is one of the major epigenetic modifications by which gene expression is regulated. Acetylation of histones is mediated by histone acetyl transferases (HATs) that exist as multisubunit complex. The alteration/deficiency in activation 3 (Ada3) protein was discovered as an essential component of various HAT complexes and later on we identified Ada3 as a novel human papilloma virus E6 oncoprotein binding protein. We have previously demonstrated that Ada3 regulates the function of p53 by mediating its acetylation and recent findings from our laboratory show that Ada3 is a novel cell cycle regulator and is crucial for maintaining the genomic stability. Although Ada3 is an essential mediator of histone acetylation it does not have HAT activity per se and how Ada3 performs its function remains unresolved. Our recent studies demonstrate that Ada3 itself is acetylated by GCN5 and p300 both in in-vitro and in-vivo assays. Significantly, inhibition of acetylation by garcinol dramatically decreases Ada3 protein levels, suggesting that acetylation stabilizes Ada3 protein. Current studies are directed towards identification of potential acetylation sites in Ada3 through mutational analyses. Notably, inhibition of class III but not class I and II histone deacetylases (HDACs) enhanced Ada3 acetylation. Further investigation reveals that Ada3 specifically interacts with SIRT1, a member of class III HDAC, indicating that SIRT1 might deacetylate Ada3. Overall our findings suggest that Ada3 exists in dynamic balance of acetylation and deacetylation, and its cell cycle regulatory function may depend on Ada3 acetylation and deacetylation. Citation Format: Shashank Srivastava, Shakur Mohibi, Hamid Band, Vimla Band. Acetylation of alteration/deficiency in activation 3 (Ada3) is essential for its stability and function. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5300. doi:10.1158/1538-7445.AM2014-5300