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SIRT6 and the disease of aging Mark Devries Outline • Background – Sirtuin biology – SIRT6 role in aging • Results – – – – – – – • Phylogeny Protein domains Phenotype DNA motifs Possible protein modifications Chemical activators Protein interactions Future directions Function Histone Deacetylases (HDAC) • • 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 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, 6274. 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, 161164. doi:10.1016/S0092-8674(01)00305-1