SIRT1 is a mammalian homolog of the yeast Sir2 protein, which functions as a histone deacetylase. Studies show that SIRT1 deacetylates the tumor suppressor p53, thereby inhibiting apoptosis and cellular senescence. In this study, researchers generated SIRT1-deficient mice to investigate its role in normal cells. Both SIRT1 mutant mice and cells exhibited similar phenotypes, including developmental defects in the retina and heart, and postnatal survival issues. SIRT1-deficient cells showed increased p53 acetylation after DNA damage and higher thymocyte apoptosis following ionizing radiation. However, in SIRT1-deficient embryonic fibroblasts, p53 hyperacetylation was not accompanied by increased p21 induction or DNA damage sensitivity. These findings suggest that endogenous SIRT1 regulates p53 acetylation and p53-dependent apoptosis, and is essential for specific developmental processes. In yeast, Sir2 functions as a histone deacetylase and is involved in chromatin silencing, DNA repair, and genomic stability. Sir2 deficiency leads to defects in transcriptional and recombinational silencing, senescence, and DNA repair. SIRT1, the mammalian homolog of Sir2, is involved in regulating chromatin silencing, genomic stability, and cellular senescence. However, SIRT1 deficiency in mice did not result in global gene silencing defects, but instead led to persistent eyelid closure and infertility. SIRT1 deficiency also resulted in early postnatal lethality, though the cause was unclear. Several studies have implicated SIRT1 in regulating the tumor suppressor p53. p53 is stabilized and activated in response to DNA damage, triggering apoptosis and cell-cycle arrest. SIRT1 can deacetylate p53, which correlates with p53 stabilization and activation. SIRT1 overexpression inhibits p53 transcriptional activity and apoptosis, while a catalytically inactive SIRT1 protein potentiates these responses. However, the effects of SIRT1 overexpression may not fully represent its physiological role. To study SIRT1 function, researchers used gene targeting to generate two SIRT1 mutations: one expressing a mutant protein lacking part of the catalytic domain, and one eliminating all protein expression. These mutations allowed comparison of potential dominant-negative effects with complete loss of SIRT1 expression. The findings show that endogenous SIRT1 plays critical roles during development and regulates p53 acetylation. SIRT1-deficient mice exhibited developmental defects, including exencephaly, cardiac abnormalities, and retinal defects. These defects suggest that SIRT1 is important for cardiac septation and eye morphogenesis. SIRT1-deficient mice also showed increased p53 acetylation after DNA damage, which was not accompanied by increased p21 induction or DNA damage sensitivity.SIRT1 is a mammalian homolog of the yeast Sir2 protein, which functions as a histone deacetylase. Studies show that SIRT1 deacetylates the tumor suppressor p53, thereby inhibiting apoptosis and cellular senescence. In this study, researchers generated SIRT1-deficient mice to investigate its role in normal cells. Both SIRT1 mutant mice and cells exhibited similar phenotypes, including developmental defects in the retina and heart, and postnatal survival issues. SIRT1-deficient cells showed increased p53 acetylation after DNA damage and higher thymocyte apoptosis following ionizing radiation. However, in SIRT1-deficient embryonic fibroblasts, p53 hyperacetylation was not accompanied by increased p21 induction or DNA damage sensitivity. These findings suggest that endogenous SIRT1 regulates p53 acetylation and p53-dependent apoptosis, and is essential for specific developmental processes. In yeast, Sir2 functions as a histone deacetylase and is involved in chromatin silencing, DNA repair, and genomic stability. Sir2 deficiency leads to defects in transcriptional and recombinational silencing, senescence, and DNA repair. SIRT1, the mammalian homolog of Sir2, is involved in regulating chromatin silencing, genomic stability, and cellular senescence. However, SIRT1 deficiency in mice did not result in global gene silencing defects, but instead led to persistent eyelid closure and infertility. SIRT1 deficiency also resulted in early postnatal lethality, though the cause was unclear. Several studies have implicated SIRT1 in regulating the tumor suppressor p53. p53 is stabilized and activated in response to DNA damage, triggering apoptosis and cell-cycle arrest. SIRT1 can deacetylate p53, which correlates with p53 stabilization and activation. SIRT1 overexpression inhibits p53 transcriptional activity and apoptosis, while a catalytically inactive SIRT1 protein potentiates these responses. However, the effects of SIRT1 overexpression may not fully represent its physiological role. To study SIRT1 function, researchers used gene targeting to generate two SIRT1 mutations: one expressing a mutant protein lacking part of the catalytic domain, and one eliminating all protein expression. These mutations allowed comparison of potential dominant-negative effects with complete loss of SIRT1 expression. The findings show that endogenous SIRT1 plays critical roles during development and regulates p53 acetylation. SIRT1-deficient mice exhibited developmental defects, including exencephaly, cardiac abnormalities, and retinal defects. These defects suggest that SIRT1 is important for cardiac septation and eye morphogenesis. SIRT1-deficient mice also showed increased p53 acetylation after DNA damage, which was not accompanied by increased p21 induction or DNA damage sensitivity.