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Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence
Emma Langley1, Mark Pearson, Mario Faretta
1Wellcome Institute/Cancer Research UK and Department of Pathology, University of Cambridge, Tennis Court Road, CB2 1QR, UK.
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.
Insights
The human Sir2 homolog, SIRT1, deacetylates and represses p53, a key protein in cellular senescence. SIRT1 antagonizes PML-induced p53 acetylation, rescuing premature cellular senescence.
Area of Science:
- Molecular Biology
- Cellular Biology
- Epigenetics
Background:
- The yeast Sir2 protein is a conserved NAD-dependent histone deacetylase regulating lifespan.
- SIRT1 is the human homolog of yeast Sir2.
- p53 is a crucial tumor suppressor protein involved in cellular senescence.
Purpose of the Study:
- To investigate the role of human SIRT1 in mammalian cells.
- To determine if SIRT1 interacts with p53 and modulates its function.
- To explore SIRT1's role in cellular senescence.
Main Methods:
- Overexpression of PML or oncogenic Ras (Ha-rasV12) in mammalian cells.
- Co-immunoprecipitation to assess protein interactions.
- Western blotting to detect protein acetylation.
- Cellular senescence assays.
Main Results:
- SIRT1 is recruited to PML nuclear bodies upon PML or Ha-rasV12 overexpression.
- SIRT1 binds to and deacetylates p53.
- SIRT1 represses p53-mediated transactivation.
- SIRT1 antagonizes PML-induced p53 acetylation and rescues PML-mediated premature cellular senescence.
Conclusions:
- SIRT1 is a novel negative regulator of p53 function.
- SIRT1 deacetylase activity modulates cellular senescence.
- SIRT1 plays a critical role in the regulation of p53 and cellular senescence pathways.