Negative control of p53 by Sir2α promotes cell survival under stress

The NAD-dependent histone deacetylation of Sir2 connects cellular metabolism with gene silencing as well as aging in yeast. Here, we show that mammalian Sir2 alpha physically interacts with p53 and attenuates p53-mediated functions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2 alpha, and also enhances the p53 acetylation levels in vivo. Furthermore, Sir2 alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2 alpha point mutant increases the sensitivity of cells in the stress response. Thus, our findings implicate a p53 regulatory pathway mediated by mammalian Sir2 alpha. These results have significant implications regarding an important role for Sir2 alpha in modulating the sensitivity of cells in p53-dependent apoptotic response and the possible effect in cancer therapy.