Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence

Emma Langley, Mark Pearson, Mario Faretta, Uta Maria Bauer, Roy A. Frye, Saverio Minucci, Pier Giuseppe Pelicci, Tony Kouzarides

Research output: Contribution to journalArticle

664 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2383-2396
Number of pages14
JournalEMBO Journal
Volume21
Issue number10
DOIs
Publication statusPublished - May 15 2002

Fingerprint

Cell Aging
Nuclear Proteins
Proteins
Acetylation
Histone Deacetylases
Fibroblasts
Saccharomycetales
Fungal Proteins
NAD
Yeast
Chromatin
Transcriptional Activation
Cells
Promyelocytic Leukemia Protein
Up-Regulation
Embryonic Structures

Keywords

  • NAD-dependent deacetylase
  • p53
  • PML nuclear bodies
  • Senescence
  • SIRT1

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. / Langley, Emma; Pearson, Mark; Faretta, Mario; Bauer, Uta Maria; Frye, Roy A.; Minucci, Saverio; Pelicci, Pier Giuseppe; Kouzarides, Tony.

In: EMBO Journal, Vol. 21, No. 10, 15.05.2002, p. 2383-2396.

Research output: Contribution to journalArticle

Langley, Emma ; Pearson, Mark ; Faretta, Mario ; Bauer, Uta Maria ; Frye, Roy A. ; Minucci, Saverio ; Pelicci, Pier Giuseppe ; Kouzarides, Tony. / Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. In: EMBO Journal. 2002 ; Vol. 21, No. 10. pp. 2383-2396.
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