Sirtuin 6 (SIRT6 or Sirt6) is a stress responsive protein deacetylase and mono-ADP ribosyltransferase enzyme encoded by the SIRT6 gene. SIRT6 functions in multiple molecular pathways related to aging, including DNA repair, telomere maintenance, glycolysis and inflammation.
|, SIR2L6, sirtuin 6|
Studies in mice have revealed that Sirt6 is essential for post-natal development and survival. Sirt6 knock-out mice, in which the gene encoding Sirt6 has been disrupted, exhibit a severe progeria, or premature aging syndrome, characterized by spinal curvature, greying of the fur, lymphopenia and low levels of blood glucose. The lifespan of Sirt6 knock-out mice is typically one to three months, dependent upon the strain in which the Sirt6 gene has been deleted. By contrast, wild type mice, which retain expression of Sirt6, exhibit a maximum lifespan of two to four years.
Mice which have been genetically engineered to overexpress, or produce more, Sirt6 protein exhibit an extended maximum lifespan. This lifespan extension, of about 15–16 percent, is observed only in male mice. Reciprocal regulation between SIRT6 and miRNA-122 controls liver metabolism and Predicts Hepatocarcinoma prognosis by study of Haim Cohen's lab with mice. they found that SIRT6 and miR-122 negatively regulate each other's expression. The study found SIRT6 was shown to act as a tumor suppressor that blocks the Warburg effect in cancer cells.
SIRT6 is a chromatin-associated protein that is required for normal base excision repair of DNA damage in mammalian cells. Deficiency of SIRT6 in mice leads to abnormalities that overlap with aging-associated degenerative processes.
SIRT6 also promotes the repair of DNA double-strand breaks by the process of non-homologous end joining. SIRT6 stabilizes the repair protein DNA-PKcs (DNA-dependent protein kinase catalytic subunit) at chromatin sites of damage.
As normal human fibroblasts replicate and progress towards replicative senescence the capability to undergo homologous recombinational repair (HRR) declines. However, over-expression of SIRT6 in “middle-aged” and pre-senescent cells strongly stimulates HRR. This effect depends on the mono-ADP ribosylation activity of poly(ADP-ribose) polymerase (PARP1). SIRT6 also rescues the decline in base excision repair of aged human fibroblasts in a PARP1 dependent manner. These findings suggest that SIRT6 expression may slow the aging process by facilitating DNA repair (see DNA damage theory of aging).
The medical and therapeutic relevance of SIRT6 in humans remains unclear. SIRT6 may be an attractive drug target for pharmocological activation in several diseases. Because SIRT6 attenuates glycolysis and inflammation, the gene is of medical interest in the context of several diseases, including diabetes and arthritis. Additionally, SIRT6 may be relevant in the context of cancer. Several studies have indicated that SIRT6 is selectively inactivated during oncogenesis in a variety of tumor types; a separate study demonstrated that SIRT6 overexpression was selectively cytotoxic to cancer cells. Neurodegenerative diseases in seniors (including Alzheimer's) appear concurrently with low levels of SIRT6.
Sirt6 deacetylation activity can be stimulated by high concentrations (several hundred micromolar) of fatty acids, and more potently by a first series of synthetic activators based on a pyrrolo[1,2-a]quinoxaline scaffold. Crystal structures of Sirt6/activator complexes show that the compounds exploit a SIRT6 specific pocket in the enzyme's substrate acyl binding channel.
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