Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence.
The yeast Sir2 protein mediates chromatin silencing through an intrinsic NAD-dependent histone deacetylase activity. Sir2 is a conserved protein and was recently shown to regulate lifespan extension both in budding yeast and worms. Here, we show that SIRT1, the human Sir2 homolog, is recruited to the promyelocytic leukemia protein (PML) nuclear bodies of mammalian cells upon overexpression of either PML or oncogenic Ras (Ha-rasV12). SIRT1 binds and deacetylates p53, a component of PML nuclear bodies, and it can repress p53-mediated transactivation. Moreover, we show that SIRT1 and p53 co-localize in nuclear bodies upon PML upregulation. When overexpressed in primary mouse embryo fibroblasts (MEFs), SIRT1 antagonizes PML-induced acetylation of p53 and rescues PML-mediated premature cellular senescence. Taken together, our data establish the SIRT1 deacetylase as a novel negative regulator of p53 function capable of modulating cellular senescence.
Langley
Emma
E
Wellcome Institute/Cancer Research UK and Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QR, UK.
Pearson
Mark
M
Faretta
Mario
M
Bauer
Uta-Maria
UM
Frye
Roy A
RA
Minucci
Saverio
S
Pelicci
Pier Giuseppe
PG
Kouzarides
Tony
T
D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D011994:Recombinant Proteins / Q000378:metabolism; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins; D013737:Testis / Q000166:cytology / Q000201:enzymology; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D011994:Recombinant Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C087778:SIR2 protein, S cerevisiae; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins; D006655:Histone Deacetylases