Sirt1 knockout: Sirt1, a protein deacetylase, is a tumor suppressor that promotes genome stability and regulates proteins involved in energy metabolism.
Yeast Sir2, a nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, has been implicated in chromatin silencing, longevity and genome stability. Mammals contain a family of related deacetylases, the sirtuins, of which 7 have been identified. Sirt1 is the closest mammalian orthologue of yeast Sir 2. The Sirt1 gene in mice was disrupted by homologous recombination in embryonic stem cells. The majority of Sirt1 (-/-) embryos die between E9.5 and E14.5, displaying altered histone modification, increased chromosomal aberrations, and impaired DNA damage repair. Tumor formation was increased in mutant tissues in Sirt1(+/-): p53(+/-) double heterozygotes, indicating that full levels of Sirt1 are necessary for tumor suppression. Tumorigenesis is reduced by treatment with the polyphenol, resveratrol, which activates Sirt1. Sirt1 may act as a tumor suppressor by promoting DNA damage repair and maintaining genome integrity. Sirt1also is involved in the regulation of proteins involved in energy metabolism, and components of the circadian clock.