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SIRT6 and the disease of aging
Mark Devries
Outline
• Background
– Sirtuin biology
– SIRT6 role in aging
• Results
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Phylogeny
Protein domains
Phenotype
DNA motifs
Possible protein modifications
Chemical activators
Protein interactions
Future directions
Function
Histone Deacetylases (HDAC)
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Class I and II
– Zinc dependant deacetylase
Class III
– NAD+ dependant deacetylase
– SIRT6 has deacetylase activity (Du et al., 2009)
Sirtuin Family
SIRT6 Protein
• 355 AA protein
• localizes to nucleus
• Interacts NF-kB (Kawahara et al., 2008) and
deacetylates H3K9 (Michishita et al., 2008)
SIRT 6 phenotype
Phenotype
• Shorter lifespan
• Genomic instability
Mostoslavsky et al 2006
What are the signs SIRT6 leads
to aging phenotype?
• Increase expression of aging genes
• Decreased IGF-1 levels
• Increased genomic instability
• Other signs of aging related disease
My findings on SIRT6
Phylogeny
T-Coffee
Protein domain
• Sirtuin domain
– Rossman fold
– Cystine residues
Picture retrieved from www.topsan.org
Phenotype
DNA motifs
Possible protein modifications
Protein modifications
Chemical
• No inhibitors or activators
• Resveratrol an activator?
• Room for discovery
How much resveratrol does it take to activate Sirtuins?
•200uM concentration usually for activation
•Which equal 1.824g of resveratrol
• 12,160 glasses of wine
Protein interaction
Summary
• Numerous DNA motifs ( Myc, Rel, MZF1)
• Many sites of phosphorlation/ Sumoylation
• No known activators or inhibitors
• Possible interaction with ELF5
Future directions
• Co-immunoprecipitation for interaction with
ELF5
• MS to see if SIRT6 is modified
• Western blots to determine if sumolated
• Chemical library screens to determine
new inhibitors and activators
References
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Michishita, E., McCord, R.A., Berber, E., Kioi, M., Padilla-Nash, H., Damian, M., Cheung, P.,
Kusumoto, R., Kawahara, T.L., Barrett, J.C., et al. (2008). SIRT6 is a histone h3 lysine9
deacetylase that modulates telomeric chromatin. Nature 452, 492-496.
doi:10.1038/nature06736
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Mostoslavsky, R., Chua, K.F., Lombard, D.B., Pang, W.W., Fischer, M.R., Gellon, L., Liu, P.,
Mostoslavsky, G., Franco, S., Murphy, M.M., et al. (2006). Genomic instability and aging like
phenotype in the absence of mammalian SIRT6. Cell 124, 315-329.
doi:10.1016/j.cell.2005.11.044
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Kawahara, T.L., Michishita, E., Adler, A.S., Damian, Mara., Berber, E., Lin, Meihong., McCord,
R.A., Ongaigui, K.C., Boxer, L.D., Chang, H.Y., Chua, K.F. (2008). SIRT6 links histone H3 lysine 9
deacetylation to NF-kB-dependent gene expression and organismal life span. Cell 136, 6274. doi: 10.1016/j.cell.2008.10.052
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Sauve A.A., Celic I., Avalos J., Deng H., Boeke J.D., Schramm V.L. (2001). Chemistry of gene
silencing: the mechanism of NAD+-dependent deacetylation reactions. Biochemistry
40:15456-15463 doi: 10.1021/bi011858j
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Dutnail, R.N., Pillus, L. (2001). Deciphering NAD-Dependent Deacetylases. Cell 105, 161164. doi:10.1016/S0092-8674(01)00305-1