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Human SIR2 deacetylates p53 and antagonizes PML/p53‐induced cellular senescence
Author(s) -
Langley Emma,
Pearson Mark,
Faretta Mario,
Bauer UtaMaria,
Frye Roy A.,
Minucci Saverio,
Pelicci Pier Giuseppe,
Kouzarides Tony
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/21.10.2383
Subject(s) - biology , transactivation , promyelocytic leukemia protein , microbiology and biotechnology , nuclear protein , gene silencing , acetylation , chromatin , histone deacetylase , downregulation and upregulation , histone , sirtuin 1 , histone deacetylase 2 , transcription factor , biochemistry , gene
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.