Negative control of p53 by Sir2 alpha promotes cell survival under stress

The NAD-dependent histone deacetylation of Sir2 connects cellular metabolis m with gene silencing as well as aging in yeast. Here, we show that mammali an Sir2 alpha physically interacts with p53 and attenuates p53-mediated fun ctions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylati on induced by Sir2 alpha, and also enhances the p53 acetylation levels in v ivo. Furthermore, Sir2 alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2 alpha poin t mutant increases the sensitivity of cells in the stress response. Thus, o ur findings implicate a p53 regulatory pathway mediated by mammalian Sir2 a lpha. These results have significant implications regarding an important ro le for Sir2 alpha in modulating the sensitivity of cells in p53-dependent a poptotic response and the possible effect in cancer therapy.