Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice

Abstract

SIRT1 is a mammalian homolog of the Saccharomyces cerevisiae chromatin silencing factor Sir2. Dominant-negative and overexpression studies have implicated a role for SIRT1 in deacetylating the p53 tumor suppressor protein to dampen apoptotic and cellular senescence pathways. To elucidate SIRT1 function in normal cells, we used gene-targeted mutation to generate mice that express either a mutant SIRT1 protein that lacks part of the catalytic domain or has no detectable SIRT1 protein at all. Both types of SIRT1 mutant mice and cells had essentially the same phenotypes. SIRT1 mutant mice were small, and exhibited notable developmental defects of the retina and heart, and only infrequently survived postnatally. Moreover, SIRT1-deficient cells exhibited p53 hyperacetylation after DNA damage and increased ionizing radiationinduced thymocyte apoptosis. In SIRT1-deficient embryonic fibroblasts, however, p53 hyperacetylation after DNA damage was not accompanied by increased p21 protein induction or DNA damage sensitivity. Together, our observations provide direct evidence that endogenous SIRT1 protein regulates p53 acetylation and p53-dependent apoptosis, and show that the function of this enzyme is required for specific developmental processes.

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

“…Sirtuin deficiency has been previously associated with reduced lifespan; for example, SirT6 −/− mice die within the first month of life with clear signs of accelerated aging (Mostoslavsky et al , 2006). However, only SIRT1 deficiency has been associated with severe developmental defects (Cheng et al , 2003; McBurney et al , 2003; Wang et al , 2008a). Therefore, our data expand the role of sirtuins in embryonic development.…”

“…As this regulation fails, genome integrity can diminish, resulting in devastating consequences on cellular fitness, cumulatively leading to organismal aging. Indeed, numerous studies from yeast to mice support a role for sirtuins in the amelioration of human aging‐related pathologies (Guarente, 2013), and its deletion is associated with genome instability and compromised organismal viability (Cheng et al , 2003; McBurney et al , 2003; Mostoslavsky et al , 2006; Wang et al , 2008a; Serrano et al , 2013). …”

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

“…As shown in Figure 1e, knocking down SIRT2 significantly increased FOXO3 protein stability. In order to test if SIRT1 regulates FOXO3 protein abundance in vivo, we detected FOXO3 protein levels in the livers of SIRT1 knockout mice (Cheng et al, 2003). As shown in Figure 1f, ablation of SIRT1 elevated abundance of FOXO3 in liver.…”

Sirtuin‐mediated deacetylation pathway stabilizes Werner syndrome protein

“…S1. Sirt1-heterozygous mice, designated Sirt1 +/D , were generated in a previous study [13], and homozygous mutant offspring (Sirt1 D/D ) from heterozygous parents were generated by in vitro fertilization and embryo transfer (IVF-ET).…”