Negative control of p53 by Sir2alpha 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 Sir2alpha physically interacts with p53 and attenuates p53-mediated functions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2alpha, and also enhances the p53 acetylation levels in vivo. Furthermore, Sir2alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2alpha point mutant increases the sensitivity of cells in the stress response. Thus, our findings implicate a p53 regulatory pathway mediated by mammalian Sir2alpha. These results have significant implications regarding an important role for Sir2alpha in modulating the sensitivity of cells in p53-dependent apoptotic response and the possible effect in cancer therapy.
Luo
J
J
Institute of Cancer Genetics and Department of Pathology, College of Physicians & Surgeons, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA.
Nikolaev
A Y
AY
Imai
S
S
Chen
D
D
Su
F
F
Shiloh
A
A
Guarente
L
L
Gu
W
W
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D004249:DNA Damage; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009243:NAD / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy; D009536:Niacinamide / Q000494:pharmacology; D018384:Oxidative Stress; D017354:Point Mutation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D019014:fas Receptor / Q000378:metabolism
D018076:DNA, Complementary; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D009243:NAD; D009536:Niacinamide; D011065:Poly(ADP-ribose) Polymerases; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases