Sirtuin 6 (SIRT6) is a member of the sirtuin family of proteins, a class of NAD+-dependent enzymes that have been linked to cellular aging and longevity. This protein is predominantly located in the cell's nucleus, where it functions as a master regulator of several critical physiological processes through its unique enzymatic activities. Research has established SIRT6 as a key player in maintaining genomic integrity, regulating cellular metabolism, influencing immune responses, and playing a complex, context-dependent role in cancer.
The Multifaceted Enzymatic Activities of SIRT6
As an enzyme, SIRT6 exhibits several types of activity that allow it to modify a wide range of protein and histone substrates. These post-translational modifications are central to its regulatory functions.
- Deacetylation: SIRT6 can remove acetyl groups from histone proteins, particularly at sites like H3K9, H3K18, and H3K56, influencing chromatin structure and gene expression. This activity is crucial for gene silencing and maintaining genomic stability.
- Defatty-acylation: Unlike many sirtuins, SIRT6 is highly efficient at removing long-chain fatty acyl groups from lysine residues. This function has been linked to the regulation of protein secretion, such as the inflammatory cytokine TNF-α, and cellular signaling pathways involving proteins like R-Ras2.
- Mono-ADP-ribosylation: SIRT6 also transfers ADP-ribose moieties to proteins, including itself. This activity is particularly important for its role in DNA repair and in silencing repetitive genetic elements.
SIRT6 in DNA Repair and Genomic Stability
One of the most critical roles of SIRT6 is its involvement in protecting the genome from damage. Its functions in DNA repair and maintaining genomic stability are extensive and well-documented.
SIRT6 as a DNA Damage Sensor
SIRT6 acts as a direct sensor for DNA double-strand breaks (DSBs), the most deleterious type of DNA damage. It is rapidly recruited to damage sites within seconds, even before other signaling pathways are fully activated. Upon binding to broken DNA ends, SIRT6 initiates the DNA damage response (DDR), signaling for the recruitment of downstream repair factors. This is a critical first step in both non-homologous end joining (NHEJ) and homologous recombination (HR) pathways.
Chromatin Remodeling and Gene Silencing
SIRT6 influences chromatin structure to facilitate DNA repair. For instance, by deacetylating H3K56, SIRT6 recruits the chromatin remodeler SNF2H, which increases accessibility to the damaged DNA and allows repair factors like BRCA1 and 53BP1 to bind effectively. Furthermore, SIRT6 plays a key role in silencing retrotransposons like LINE-1 by mono-ADP-ribosylating KAP1, which promotes the formation of repressive heterochromatin. This silencing effect is important for preventing genomic instability.
Regulation of Metabolism by SIRT6
SIRT6 is a potent regulator of both glucose and lipid metabolism, and its activity links cellular energy status to overall physiological health. SIRT6 knockout mice exhibit severe metabolic defects, including hypoglycemia, demonstrating its fundamental role in maintaining metabolic balance.
Key Metabolic Pathways
- Inhibiting Glycolysis: SIRT6 acts as a corepressor of the transcription factor hypoxia-inducible factor 1α (HIF-1α), downregulating the expression of glycolytic genes like GLUT1 and PFK1. By promoting oxidative phosphorylation, SIRT6 prevents the metabolic shift known as the Warburg effect, which is common in cancer cells.
- Controlling Gluconeogenesis: SIRT6 regulates glucose production in the liver, in part by deacetylating the transcription factor FoxO1, which triggers its nuclear export and inhibits the expression of gluconeogenic genes.
- Modulating Lipid Metabolism: The enzyme regulates lipid homeostasis by repressing lipogenic genes and promoting fatty acid β-oxidation. Liver-specific SIRT6 deletion in mice leads to fatty liver, while overexpression protects against fat accumulation.
Connection to Aging and Longevity
Evidence from animal studies strongly suggests a link between SIRT6 and aging. Loss of SIRT6 in mice leads to a premature aging phenotype with a dramatically shortened lifespan, while its overexpression can extend the lifespan of male mice. The anti-aging effects are attributed to its roles in maintaining genomic stability and regulating metabolism. By efficiently repairing DNA damage and preserving telomere integrity, SIRT6 mitigates the accumulation of cellular damage that drives the aging process. Its control over energy metabolism also contributes to its anti-aging properties, with overexpression mimicking some of the health benefits observed with calorie restriction.
SIRT6's Dual Role in Cancer
The function of SIRT6 in cancer is complex and depends heavily on the specific context of the tumor and cellular environment. It can act as a tumor suppressor in some cancers while promoting tumor growth in others.
Anti-tumorigenic vs. Pro-tumorigenic Functions
| Feature | Anti-tumorigenic Role (Tumor Suppressor) | Pro-tumorigenic Role (Oncogene) |
|---|---|---|
| Mechanism | Suppresses glycolysis and the Warburg effect via HIF-1α repression; promotes DNA damage-induced apoptosis. | Promotes DNA repair in certain cancer cells, protecting them from chemotherapy; enhances migration and invasion in other contexts. |
| Expression | Often downregulated in cancers like bladder cancer and pancreatic cancer. | Overexpressed in certain cancers like renal cell carcinoma and metastatic melanoma. |
| Outcome | Leads to reduced cell proliferation and tumor growth, improving prognosis. | Associated with increased aggressiveness, metastasis, and poor prognosis. |
This duality makes SIRT6 a challenging but intriguing therapeutic target for cancer. The strategy of either activating or inhibiting SIRT6 would need to be tailored to the specific cancer type and stage.
Role in the Immune System
SIRT6 also regulates the immune system, primarily influencing inflammatory responses and immune cell function. Its effects can be complex, showing both anti-inflammatory and pro-inflammatory potential depending on the specific cellular context and stimulus. For example, SIRT6 negatively regulates NF-κB, a key transcription factor in inflammation, but can also promote the secretion of the pro-inflammatory cytokine TNF-α through its defatty-acylation activity. Its role in regulating immunometabolism further impacts the differentiation and function of immune cells like macrophages and T cells.
Conclusion
SIRT6 is a central hub for maintaining cellular homeostasis through its diverse enzymatic activities, primarily localized in the nucleus. As a guardian of the genome, it senses and initiates the repair of DNA damage and silences problematic genetic elements. As a metabolic conductor, it coordinates glucose and lipid metabolism to promote energy efficiency and longevity. The profound effects of SIRT6 on aging, metabolism, and genomic integrity highlight its significance in health and disease. However, its dual, context-dependent role in cancer and its complex effects on the immune system illustrate the need for personalized therapeutic approaches when targeting this remarkable enzyme. Its central role in these fundamental biological processes positions SIRT6 as a promising target for future therapeutic interventions.
