It has been reported that p53 acetylation, which promotes cellular senescence, can be regulated by the NAD+-dependent deacetylase SIRT1, the human homolog of yeast Sir2, a protein that modulates lifespan. To clarify the role of SIRT1 in cellular senescence induced by oxidative stress, we treated normal human diploid fibroblast TIG-3 cells with H2O2 and examined DNA cleavage, depletion of intracellular NAD+, expression of p21, SIRT1, and acetylated p53, cell cycle arrest, and senescence-associated β-galactosidase (SA-β-gal) activity. DNA cleavage was observed immediately in TIG-3 cells treated with H2O2, though no cell death was observed. NAD+ levels in TIG-3 cells treated with H2O2 were also decreased significantly. Pre-incubation with the poly (ADP-ribose) polymerase (PARP) inhibitor resulted in preservation of intracellular NAD+ levels. The amount of acetylated p53 was increased in TIG-3 cells at 4h after H2O2 treatment, while there was little to no decrease in SIRT1 protein expression. The expression level of p21 was increased at 12h and continued to increase for up to 24h. Additionally, exposure of TIG-3 cells to H2O2 induced cell cycle arrest at 24h and increased SA-β-gal activity at 48h. This pathway likely plays an important role in the acceleration of cellular senescence by oxidative stress.

Keywords:
SIRT1, p53, H2O2, DNA damage, Cellular senescence, NAD+
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© 2007 S. Karger AG, Basel
2007
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