SIRT6

Official Full Name

sirtuin 6

Organism

Homo sapiens

GeneID

51548

Background

This gene encodes a member of the sirtuin family of NAD-dependent enzymes that are implicated in cellular stress resistance, genomic stability, aging and energy homeostasis. The encoded protein is localized to the nucleus, exhibits ADP-ribosyl transferase and histone deacetylase activities, and plays a role in DNA repair, maintenance of telomeric chromatin, inflammation, lipid and glucose metabolism. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

Synonyms

SIR2L6; hSIRT6;

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Detailed Information

The SIRT6 gene encodes Sirtuin 6 and is located on human chromosome 19p13.3. It is a member of the sirtuin family of NAD⁺-dependent deacetylases (SIRT1–SIRT7). All family members share a conserved NAD⁺-binding catalytic domain but differ in subcellular localization and substrate specificity. SIRT6 is primarily localized in the nucleus and tightly associates with chromatin. Compared to classical class III histone deacetylases, SIRT6 exhibits relatively weak histone deacetylase activity but possesses robust ADP-ribosyltransferase activity and long-chain fatty acyl deacylase activity. SIRT6 is widely expressed across multiple tissues, and its activity is regulated by NAD⁺ levels, nutritional status, and cellular stress. Transcriptional and post-translational modifications, such as phosphorylation and SUMOylation, together establish a finely tuned regulatory network for SIRT6.

Figure 1. SIRT6 promotes fatty acid oxidation by multiple mechanisms. (Dong XC. 2023)

Biological Significance

SIRT6 is a key regulator of genomic stability, metabolic homeostasis, and aging. In DNA damage repair, SIRT6 is rapidly recruited to sites of DNA double-strand breaks, where it deacetylates H3K9 and H3K56, facilitating the recruitment of critical proteins for non-homologous end joining (NHEJ) and homologous recombination (HR), thereby efficiently initiating repair. SIRT6 also deacetylates non-histone substrates such as DDB2 and p53, further coordinating the repair process. In telomere maintenance, SIRT6 preserves telomeric heterochromatin integrity by regulating H3K9ac and H3K56ac, preventing aberrant chromosomal end structures.

In metabolic regulation, SIRT6 functions as a negative regulator of glycolysis and lipid metabolism. It acts as a co-repressor of HIF1α to suppress glycolysis-related gene expression and directly deacetylates PKM2 to inhibit its activity, thereby restraining the Warburg effect in tumor cells. In the liver, SIRT6 deacetylates FOXO1 and GCN5 to inhibit gluconeogenesis, while modulating PPARGC1α and NCOA2 to promote fatty acid β-oxidation and suppress lipogenesis. Its de-fatty-acylation activity regulates the membrane localization and secretion of Ras-related protein RRAS2 and TNF, influencing signaling and inflammatory responses. Additionally, SIRT6 regulates gene silencing and chromatin structure via ADP-ribosylation of KAP1 and BAF170. Collectively, SIRT6 integrates energy metabolism, stress responses, and epigenetic regulation through multiple enzymatic activities, providing a molecular basis for delaying aging and maintaining healthspan.

Figure 2. SIRT6 promotes fatty acid oxidation by multiple mechanisms. (Dong XC. 2023)

Clinical Relevance

SIRT6 plays a critical role in aging and age-related diseases. Studies in model organisms have shown that SIRT6 overexpression extends lifespan and mitigates age-associated pathologies, making it a promising target for anti-aging interventions. In metabolic disorders, SIRT6 deficiency is associated with obesity, insulin resistance, and type 2 diabetes, and enhancing SIRT6 activity is considered a potential strategy to improve metabolic health and treat MASLD. In the cardiovascular system, SIRT6 inhibits endothelial inflammation, delays vascular calcification, and attenuates cardiac hypertrophy, protecting against atherosclerosis and heart failure.

In oncology, SIRT6 generally functions as a tumor suppressor by inhibiting glycolysis and maintaining genomic stability, though it may exhibit context-dependent pro-survival effects. Downregulation of SIRT6 correlates with poor prognosis in colorectal, liver, and pancreatic cancers, suggesting that restoring SIRT6 function could be a novel anticancer strategy. In neurodegenerative disease models, SIRT6 demonstrates neuroprotective effects, potentially via DNA repair, attenuation of neuroinflammation, and modulation of energy metabolism.

Challenges in clinical translation mainly involve developing specific SIRT6 activators. Candidate molecules such as UBCS039 have shown preclinical potential, but their potency and specificity require optimization. Moreover, the long-term safety and potential off-target effects of systemic SIRT6 activation must be carefully evaluated. Future research will focus on tissue-specific delivery or targeting downstream effectors. As a central molecule linking metabolism, DNA repair, and aging, SIRT6 activator development holds promise for treating age-related diseases.

References

Mostoslavsky R, Chua KF, Lombard DB, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006;124(2):315-329.
Guo Z, Li P, Ge J, Li H. SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases. Aging Dis. 2022 Dec 1;13(6):1787-1822.
Dong XC. Sirtuin 6-A Key Regulator of Hepatic Lipid Metabolism and Liver Health. Cells. 2023 Feb 19;12(4):663.
Zhong L, D'Urso A, Toiber D, et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell. 2010;140(2):280-293.
Kanfi Y, Naiman S, Amir G, et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature. 2012;483(7388):218-221.

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