Genomic instability and aging-like phenotype in the absence of mammalian SIRT6.

By R. Mostoslavsky, Katrin F. Chua, D. Lombard, W. Pang, Miriam R. Fischer, L. Gellon, Pingfang Liu, G. Mostoslavsky, S. Franco, Michael M. Murphy and 21 more. Cell, 2006

1,512 citations recorded by the source corpus.

The Sir2 histone deacetylase functions as a chromatin silencer to regulate recombination, genomic stability, and aging in budding yeast. Seven mammalian Sir2 homologs have been identified (SIRT1-SIRT7), and it has been speculated that some may have similar functions to Sir2. Here, we demonstrate that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER). SIRT6-deficient mice are small and at 2-3 weeks of age develop abnormalities that include profound lymphopenia, loss of subcutaneous fat, lordokyphosis, and severe metabolic defects, eventually dying at about 4 weeks. We conclude that one function of SIRT6 is to promote normal DNA repair, and that SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes.

Subfields: Cellular and Molecular Neuroscience, Geriatrics and Gerontology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/649e351ef47f300deb82672789cb88e72b04aefc

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. D. Sinclair
2. Aviv Regev
3. E. Verdin
4. Guido Kroemer
5. Johan Auwerx
6. L. Guarente
7. V. Longo

In Geriatrics and Gerontology

1. L. Guarente
2. D. Sinclair
3. Johan Auwerx
4. E. Verdin
5. M. Haigis
6. C. Cantó
7. E. Seto
8. R. Houtkooper

In Pharmacology

1. Guido Kroemer
2. Linda Partridge
3. Liangyou Rui
4. Beth Levine

Citations in the corpus

• THE HISTONE DEACETYLASE SIRT6 IS A NOVEL TUMOR SUPPRESSOR THAT CONTROLS CANCER METABOLISM (2012, positive): “SIRT6-Deficient Cells Are Tumorigenic We have previously shown that SIRT6 protects from genomic instability (Mostoslavsky et al., 2006) and regulates aerobic glycolysis (Zhong et al.”
• Sirtuins in aging and age-related disease. (2006, background): “A recent report finds that mice lacking Sirt6 exhibit enhanced genome instability leading to a wide range of chromosomal anomalies as well as phenotypes resembling premature aging, including cachexia, kyphosis, and osteopenia (Mostoslavsky et al., 2006).”
• The Histone Deacetylase SIRT6 Regulates Glucose Homeostasis via Hif1α (2010, positive): “Glycolytic Genes as Putative SIRT6 Targets in Glucose Metabolism Based on the strong binding of SIRT6 to chromatin (Mostoslavsky et al., 2006), and the fact that SIRT6 is known to function as a histone H3K9 deacetylase (Kawahara et al.”
• The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse (2013, methodology): “We used Receiver Operating Characteristic (ROC) curves to determine optimal parameters for our classification algorithm [36].”
• Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. (2006, background): “SIRT6 KO mice also display interesting metabolic phenotypes: low levels of circulating IGF-1 and hypoglycemia that becomes progressively more severe with age (Mostoslavsky et al. 2006).”
• The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. (2010, background): “SIRT6 / mice die prematurely, displaying severe defects, such as lymphopenia, loss of sc fat, decreased bone mineral density, a profound imbalance in glucose homeostasis, and decreased IGF-I levels (124).”
• Sirtuins: critical regulators at the crossroads between cancer and aging (2007, methodology): “Proper regulation of genomic stability protects against tumor formation and aging (Lombard et al., 2005) and SIRT6 / mice show premature aging-like symptoms and die several weeks after birth (Mostoslavsky et al., 2006).”