1 / 19

SIRT6 and the disease of aging

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.

jennis
Download Presentation

SIRT6 and the disease of aging

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. SIRT6 and the disease of aging Mark Devries

  2. Outline • Background • Sirtuin biology • SIRT6 role in aging • Results • Phylogeny • Protein domains • Phenotype • DNA motifs • Possible protein modifications • Chemical activators • Protein interactions • Future directions

  3. FunctionHistone Deacetylases (HDAC) • Class I and II • Zinc dependant deacetylase • Class III • NAD+ dependant deacetylase • SIRT6 has deacetylase activity (Du et al., 2009)

  4. Sirtuin Family

  5. SIRT6 Protein • 355 AA protein • localizes to nucleus • Interacts NF-kB (Kawahara et al., 2008) and deacetylates H3K9 (Michishita et al., 2008)

  6. SIRT 6 phenotype • Phenotype • Shorter lifespan • Genomic instability Mostoslavsky et al 2006

  7. 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

  8. My findings on SIRT6

  9. Phylogeny T-Coffee

  10. Protein domain • Sirtuin domain • Rossman fold • Cystine residues Picture retrieved from www.topsan.org

  11. Phenotype

  12. DNA motifs

  13. Possible protein modifications

  14. Protein modifications

  15. 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

  16. Protein interaction

  17. Summary • Numerous DNA motifs ( Myc, Rel, MZF1) • Many sites of phosphorlation/ Sumoylation • No known activators or inhibitors • Possible interaction with ELF5

  18. Future directions • Co-immunoprecipitationfor 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

  19. 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

More Related