Sirtuin 6

Research

Sirt6 is mainly known as a deacetylase of histones H3 and H4, an activity by which it changes chromatin density and regulates gene expression. The enzymatic activity of Sirt6, as well as of the other members of the sirtuins family, is dependent upon the binding of the cofactor nicotinamide adenine dinucleotide (NAD+).

Mice which have been genetically engineered to overexpress Sirt6 protein exhibit an extended maximum lifespan. This lifespan extension, of about 15–16 percent, is observed only in male mice.

DNA repair

SIRT6 is a chromatin-associated protein that is required for normal base excision repair and double-strand break repair of DNA damage in mammalian cells. Deficiency of SIRT6 in mice leads to abnormalities that overlap with aging-associated degenerative processes.

SIRT6 promotes the repair of DNA double-strand breaks by the process of non-homologous end joining and homologous recombination. 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.

Ligands

;Activators 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.

• Among many anthocyanidins studied, cyanidin most potently stimulated activity of the SIRT6.
• SP-624 is also an activator of Sirt6.
• MDL-811
• UBCS039
• SIRT6 activator 12q

;Inhibitors

• JYQ-42
• OSS-128167

References

References

1. (July 2000). "Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins". Biochemical and Biophysical Research Communications.
2. "Entrez Gene: SIRT6 sirtuin (silent mating type information regulation 2 homolog) 6 (S. cerevisiae)".
3. (2011). "Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair". [[Aging (journal).
4. (2016). "Slowing ageing by design: the rise of NAD + and sirtuin-activating compounds". Nat Rev Mol Cell Biol.
5. (February 2012). "The sirtuin SIRT6 regulates lifespan in male mice". Nature.
6. (January 2006). "Genomic instability and aging-like phenotype in the absence of mammalian SIRT6". Cell.
7. (2019). "SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species". [[Cell (journal).
8. (2020). "Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators". [[Journal of Biological Chemistry]].
9. (January 2009). "SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair". Aging.
10. (July 2012). "Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence". Proceedings of the National Academy of Sciences of the United States of America.
11. (2015). "SIRT6 rescues the age related decline in base excision repair in a PARP1-dependent manner". Cell Cycle.
12. (October 2013). "Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins". The Journal of Biological Chemistry.
13. (January 2017). "Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules". Angewandte Chemie.
14. (29 August 2024). "SP 624".
15. (21 September 2024). "Delving into the Latest Updates on SP-624 with Synapse".
16. (March 2024). "Epigenetic modification in liver fibrosis: Promising therapeutic direction with significant challenges ahead". Acta Pharm Sin B.