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SIRT6 and the disease of aging
Mark Devries
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Outline
• Background– Sirtuin biology– SIRT6 role in aging
• Results – Phylogeny– Protein domains– Phenotype– DNA motifs– Possible protein modifications– Chemical activators– Protein interactions
• Future directions
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FunctionHistone Deacetylases (HDAC)• Class I and II
– Zinc dependant deacetylase
• Class III
– NAD+ dependant deacetylase
– SIRT6 has deacetylase activity (Du et al., 2009)
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Sirtuin Family
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SIRT6 Protein
• 355 AA protein
• localizes to nucleus
• Interacts NF-kB (Kawahara et al., 2008) and deacetylates H3K9 (Michishita et al., 2008)
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SIRT 6 phenotype
Mostoslavsky et al 2006
Phenotype
• Shorter lifespan
• Genomic instability
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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
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My findings on SIRT6
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Phylogeny
T-Coffee
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Protein domain
• Sirtuin domain– Rossman fold– Cystine residues
Picture retrieved from www.topsan.org
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Phenotype
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DNA motifs
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Possible protein modifications
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Protein modifications
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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
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Protein interaction
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Summary
• Numerous DNA motifs ( Myc, Rel, MZF1)
• Many sites of phosphorlation/ Sumoylation
• No known activators or inhibitors
• Possible interaction with ELF5
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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
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References 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
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
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, 62-74. doi: 10.1016/j.cell.2008.10.052
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
Dutnail, R.N., Pillus, L. (2001). Deciphering NAD-Dependent Deacetylases. Cell 105, 161-164. doi:10.1016/S0092-8674(01)00305-1