Regulation of the tumor suppressor protein p53 by MYST family acetyltransferases

The tumor suppressor gene TP53, is the most commonly mutated gene observed in human cancer. The TP53 gene encodes the p53 protein, which antagonizes tumorigenesis by preventing the accumulation and propagation of gene mutations. Specifically, in cells that have incurred DNA damage p53 can either arrest cell growth or initiate the cell death program, apoptosis. To evoke these biological responses p53 directly regulates the expression of genes encoding effector proteins that carry out these functions. In addition to regulating transcription, p53 also relies on transcription-independent functions to promote tumor suppressive activities such as apoptosis. The ability of p53 to engage these biological responses is influenced by its interactions with a variety of different co-factors. In particular, the MYST family acetyltransferases hMOF and TIP60 enhance the transcriptional capabilities of p53. Being that an extensive network of post-translational modifications regulates p53 activity the first aim of the study was to determine whether hMOF and TIP60 alter p53 activity through direct acetylation. Both hMOF and TIP60 acetylate p53 in the DNA-binding domain at lysine 120 (Lys 120). Acetylation of p53 at Lys120 is required for p53 to induce both transcription-dependent and -independent apoptosis. Specifically, Lys120 acetylation directs p53 to the transcriptional start sites of certain pro-apoptotic target genes to facilitate the loading and firing of RNA polymerase II. Additionally, acetylation of Lys120 is needed by p53 at mitochondria to promote transcription-independent apoptosis by assisting in the displacement of the anti-apoptotic protein MCL-1 from the pro-apoptotic protein BAK. Reinforcing the importance of Lys120 acetylation in p53's ability to suppress tumorigenesis, non-acetylatable p53 point mutations at Lys120 have been observed in human cancer. In addition to Lys120, hMOF also acetylates p53 at lysine 357 (Lys357). Depending on the situation, p53 is also acetylated at Lys357 by the acetyltransferase GCN5. While Lys357 acetylation appears to be dispensable for p53-mediated cell growth arrest and apoptosis in response to DNA damage, it may be important for other biological processes affected by p53 such as senescence or DNA repair. The data presented here provides new insight into the mechanisms that regulate p53-mediated apoptosis.