Abstract SY11-01: Knockout mouse models for sirtuins: Genome integrity, metabolism, and cancer

Abstract

Abstract In budding yeast, Sir2 is a NAD+-dependent histone deacetylase that plays a role in chromatin silencing, longevity and genomic stability. In mammals, sirtuins exist as a family of 7 members (SIRT1-7) that deacetylate histones and many nonhistone proteins. Currently, all sirtuins have been knocked out by gene targeting, and the mutant mice suffer various abnormalities in cell growth, apoptosis, neurological behavior, adaptation to calorie restriction, organ metabolism and function, and/or premature aging, highlighting critical roles of sirtuins in these biological processes. Of note, mice carrying mutations of SIRT1, SIRT2 or SIRT3 also developed cancers, predominantly in the mammary glands and the liver that are accompanied by genomic instability and/or abnormal energy metabolism. Our further analysis revealed distinct role of these siruins in maintaining genome integrity. SIRT1 mutant cells displayed altered histone modification, impaired DNA damage response, and reduced ability to repair DNA damage [1]; SIRT3 mutant cells had increased stress-induced superoxide levels and genomic instability [2]; and SIRT2 loss primarily affects mitotic functions. We found that SIRT2 plays a role in maintaining normal mitosis progression through modulating expression levels of several mitotic regulators, including Aurora-A and -B. Loss of SIRT2, consequently, causes centrosome amplification, aneuploidy, and mitotic catastrophe. SIRT2-deficient mice initially develop normally, however, suffer mammary tumors and hepatocellular carcinoma (HCC) when they become old. These data highlight how accurate maintenance of genomic integrity is critical for the suppression of tumorigenesis. Finally, we found that human breast cancer and HCC exhibit reduced levels of SIRT1-3. These results implicate SIRT1-3 as tumor suppressors in these organs.