Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice

By Ruihong Wang, Kundan Sengupta, Cuiling Li, Hyunseok Kim, Liu Cao, C. Xiao, Sangsoo Kim, Xiaoling Xu, Yin Zheng, B. Chilton and 6 more. Cancer Cell, 2008

804 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Geriatrics and Gerontology, Oncology

View Paper: https://www.semanticscholar.org/paper/19a79b31d29e25951ccf604cd7150d2ff66af877

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Citations in the corpus

The hallmarks of aging. (2013, background): “The mechanisms involved in the beneficial effects of SIRT1 are complex and interconnected, including improved genomic stability (Oberdoerffer et al., 2008; Wang et al., 2008) and enhanced metabolic efficiency (Nogueiras et al., 2012) (see ‘‘Deregulated Nutrient Sensing’’).”
SIRT1 and other sirtuins in Metabolism (2013, background): “Further, mice heterozygous for both SIRT1 and p53 developed spontaneous tumors, indicating that SIRT1 might function as a haplo-insufficient tumor suppressor [101].”
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SIRT3 is a Mitochondrial Localized Tumor Suppressor Required for Maintenance of Mitochondrial Integrity and Metabolism During Stress (2010, background): “SIRT3 Knockout Livers and MEFs Have Decreased Mitochondrial Integrity with Age It has previously been suggested that nuclear sirtuins may function as fidelity proteins that play a role in the maintenance of genomic integrity (Wang et al., 2008).”
Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. (2010, background): “M SIRT1 deficiency promotes the development of multiple tumors by disrupting genomic stability, and SIRT1 overexpression inhibits the development of colon cancer by deacetylating b-catenin (Wang et al., 2008; Firestein et al., 2008).”