Impaired DNA Damage Response, Genome Instability, and Tumorigenesis in SIRT1 Mutant Mice

Abstract

Summary In lower eukaryotes, Sir2 serves as a histone deacetylase and is implicated in chromatin silencing, longevity and genome stability. Here we mutated the SIRT1 gene, a homolog of yeast Sir2, in mice to study its function. We showed that a majority of SIRT1-null embryos died between E9.5–E14.5, displaying altered histone modification, impaired DNA damage response, and reduced ability to repair DNA damage. We demonstrated that SIRT1+/−;p53+/− mice developed tumors in multiple tissues, whereas activation of SIRT1 by resveratrol treatment reduced tumorigenesis. Finally, we showed that many human cancers exhibited reduced level of SIRT1 than their normal controls. Thus, SIRT1 acts as a tumor suppressor through its role in DNA damage response, genome integrity, and tumor suppression. Significance SIRT1 has diverse roles in various biological processes, including caloric restriction that causes changes in glucose metabolism and lifespan. The role of SIRT1 in cancer is currently under debate due to some recent different findings. It is known that calorie restriction, which activates SIRT1, extends lifespan and inhibits tumorigenesis. On the other hand, SIRT1 deacetylates p53 to decrease its activity. It was therefore hypothesized increased SIRT1 activity, although it extends lifespan, may elevate cancer risk. Here we demonstrate SIRT1 plays an important role in DNA damage response and genome integrity by maintaining proper chromatin structure and DNA damage repair foci formation. We further show that SIRT1 serves as a tumor suppressor in mice and in some types of human cancers.

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). …”

SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol

“…Accumulating evidence also point to SirT1 as having a function in cancer; however, inferences from the literature are that SirT1 has both oncogenic and tumor-suppressor activities. SirT1 was reported to be overexpressed in acute myeloid leukemia, non-melanoma skin cancer, breast cancer, colorectal carcinoma and prostate cancer (Bradbury et al, 2005;Kuzmichev et al, 2005;Hida et al, 2007;Huffman et al, 2007;Stunkel et al, 2007) and to be downregulated in glioblastoma, prostate cancer, bladder carcinoma, breast cancer, hepatocellular carcinoma and ovarian cancer (Wang et al, 2008a). It is also expressed at a high level in diffuse large B-cell lymphomas and is associated to bad prognosis (Jang et al, 2008).…”

“…Moreover, some targets of SirT1 deacetylation, including p53 (Luo et al, 2001;Vaziri et al, 2001), p73 (Dai et al, 2007), nuclear factor-kB (NF-kB) (Yeung et al, 2004;Chen et al, 2005a) and AR (Fu et al, 2006), are important proteins involved in cancer. Finally, recent reports suggest that SirT1 has a function in maintaining genome stability Wang et al, 2008a) and compromise of the genome is a hallmark of cancer.…”

“…We (McBurney et al, 2003) and others (Cheng et al, 2003;Wang et al, 2008a) have created mice carrying targeted mutations in the SirT1 gene. On an outbred genetic background, most of our SirT1-null mice survive to adulthood.…”