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  • The EMBO Journal (2002) 21, 2383 - 2396
  • doi:10.1093/emboj/21.10.2383

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

Emma Langley1, Mark Pearson2,3, Mario Faretta2, Uta-Maria Bauer1, Roy A. Frye4, Saverio Minucci2,5, Pier Giuseppe Pelicci2,6 and Tony Kouzarides1

  1. Wellcome Institute/Cancer Research UK and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
  2. European Institute of Oncology, Department of Experimental Oncology, I-20141 Milan, Italy
  3. Present address: Novartis, Oncology Department, CH-4002 Basel, Switzerland
  4. Pittsburgh V.A. Medical Center (132L), Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15240, USA
  5. University of Milan, Department of Physiology and Biochemistry I-20100 Milan, Italy
  6. FIRC Institute of Molecular Oncology, I-20100 Milan, Italy

Correspondence to:

Tony Kouzarides, E-mail: tk106@mole.bio.cam.ac.uk

Received 26 September 2001; Accepted 25 March 2002; Revised 25 March 2002

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.

  • Keywords:

    • NAD-dependent deacetylase,
    • p53,
    • PML nuclear bodies,
    • senescence,
    • SIRT1