Skip to main content
SpringerLink
Log in

Discussion

  • Chapter
  • First Online:
SIRT6 Activities in DNA Damage Repair and Premature Aging

Part of the book series: Springer Theses ((Springer Theses))

  • 240 Accesses

Abstract

This chapter chronologically discusses all three result sections in details. It helps the readers to understand how the present study corroborates with the existing literature. This section also raises questions rooting from this study, which need to be addressed with further experimentation. This is followed by point-wise conclusions drawn from this study as take-home notes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Vitiello, M., A. Zullo, L. Servillo, F.P. Mancini, A. Borriello, A. Giovane, F. Della Ragione, N. D’Onofrio, and M.L. Balestrieri. 2016. Multiple pathways of SIRT6 at the crossroads in the control of longevity, cancer, and cardiovascular diseases. Ageing Research Review.

    Google Scholar 

  2. Tasselli, L., W. Zheng, and K.F. Chua. 2016. SIRT6: Novel Mechanisms and Links to Aging and Disease. Trends in Endocrinology and Metabolism 28: 168–185.

    Article  Google Scholar 

  3. Parenti, M.D., A. Grozio, I. Bauer, L. Galeno, P. Damonte, E. Millo, G. Sociali, C. Franceschi, A. Ballestrero, S. Bruzzone, A. Del Rio, and A. Nencioni. 2014. Discovery of novel and selective SIRT6 inhibitors. Journal of Medicinal Chemistry 57: 4796–4804.

    Article  CAS  Google Scholar 

  4. Feldman, J.L., J. Baeza, and J.M. Denu. 2013. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. Journal of Biological Chemistry 288: 31350–31356.

    Article  CAS  Google Scholar 

  5. Beauharnois, J.M., B.E. Bolivar, and J.T. Welch. 2013. Sirtuin 6: a review of biological effects and potential therapeutic properties. Molecular BioSystems 9: 1789–1806.

    Article  CAS  Google Scholar 

  6. Ghosh, S., B. Liu, Y. Wang, Q. Hao, and Z. Zhou. 2015. Lamin A is an endogenous SIRT6 activator and promotes SIRT6-mediated DNA repair. Cell Report 13: 1396–1406.

    Article  CAS  Google Scholar 

  7. Kim, J.E., J. Chen, and Z. Lou. 2008. DBC1 is a negative regulator of SIRT1. Nature 451: 583–586.

    Article  CAS  Google Scholar 

  8. Kalinowski, A., P.N. Yaron, Z. Qin, S. Shenoy, M.J. Buehler, M. Losche, and K.N. Dahl. 2014. Interfacial binding and aggregation of lamin A tail domains associated with Hutchinson-Gilford progeria syndrome. Biophysical Chemistry 195: 43–48.

    Article  CAS  Google Scholar 

  9. Mostoslavsky, R., K.F. Chua, D.B. Lombard, W.W. Pang, M.R. Fischer, L. Gellon, P. Liu, G. Mostoslavsky, S. Franco, M.M. Murphy, K.D. Mills, P. Patel, J.T. Hsu, A.L. Hong, E. Ford, H.L. Cheng, C. Kennedy, N. Nunez, R. Bronson, D. Frendewey, W. Auerbach, D. Valenzuela, M. Karow, M.O. Hottiger, S. Hursting, J.C. Barrett, L. Guarente, R. Mulligan, B. Demple, G.D. Yancopoulos, and F.W. Alt. 2006. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124: 315–329.

    Article  CAS  Google Scholar 

  10. Hale, J.S., R.L. Frock, S.A. Mamman, P.J. Fink, and B.K. Kennedy. 2010. Cell-extrinsic defective lymphocyte development in Lmna(-/-) mice. PLoS ONE 5: e10127.

    Article  Google Scholar 

  11. Sullivan, T., D. Escalante-Alcalde, H. Bhatt, M. Anver, N. Bhat, K. Nagashima, C.L. Stewart, and B. Burke. 1999. Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. Journal of Cell Biology 147: 913–920.

    Article  CAS  Google Scholar 

  12. Zhou, J., H. Liu, Y. Chen, J. Wen, L. Li, and X. Wu. 2014. Expression and significance of VEGF, miR-205 and target protein Ezrin and Lamin A/C in ovarian cancer. Zhong Nan Da Xue Xue Bao Yi Xue Ban 39: 142–150.

    PubMed  Google Scholar 

  13. Wazir, U., M.H. Ahmed, J.M. Bridger, A. Harvey, W.G. Jiang, A.K. Sharma, and K. Mokbel. 2013. The clinicopathological significance of lamin A/C, lamin B1 and lamin B receptor mRNA expression in human breast cancer. Cellular and Molecular Biology Letters 18: 595–611.

    Article  CAS  Google Scholar 

  14. Sebastian, C., B.M. Zwaans, D.M. Silberman, M. Gymrek, A. Goren, L. Zhong, O. Ram, J. Truelove, A.R. Guimaraes, D. Toiber, C. Cosentino, J.K. Greenson, A.I. MacDonald, L. McGlynn, F. Maxwell, J. Edwards, S. Giacosa, E. Guccione, R. Weissleder, B.E. Bernstein, A. Regev, P.G. Shiels, D.B. Lombard, and R. Mostoslavsky. 2012. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151: 1185–1199.

    Article  CAS  Google Scholar 

  15. Gil, R., S. Barth, Y. Kanfi, and H.Y. Cohen. 2013. SIRT6 exhibits nucleosome-dependent deacetylase activity. Nucleic Acids Research 41: 8537–8545.

    Article  CAS  Google Scholar 

  16. Pan, P.W., J.L. Feldman, M.K. Devries, A. Dong, A.M. Edwards, and J.M. Denu. 2011. Structure and biochemical functions of SIRT6. Journal of Biological Chemistry 286: 14575–14587.

    Article  CAS  Google Scholar 

  17. Liszt, G., E. Ford, M. Kurtev, and L. Guarente. 2005. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. Journal of Biological Chemistry 280: 21313–21320.

    Article  CAS  Google Scholar 

  18. Kawahara, T.L., E. Michishita, A.S. Adler, M. Damian, E. Berber, M. Lin, R.A. McCord, K.C. Ongaigui, L.D. Boxer, H.Y. Chang, and K.F. Chua. 2009. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136: 62–74.

    Article  CAS  Google Scholar 

  19. Jung, E.S., H. Choi, H. Song, Y.J. Hwang, A. Kim, H. Ryu, and I. Mook-Jung. 2016. p53-dependent SIRT6 expression protects Abeta42-induced DNA damage. Scientific Reports 6: 25628.

    Article  CAS  Google Scholar 

  20. Zhang, P., B. Tu, H. Wang, Z. Cao, M. Tang, C. Zhang, B. Gu, Z. Li, L. Wang, Y. Yang, Y. Zhao, H. Wang, J. Luo, C.X. Deng, B. Gao, R.G. Roeder, and W.G. Zhu. 2014. Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. Proceedings of the National Academy of Sciences 111: 10684–10689.

    Article  CAS  Google Scholar 

  21. Ghosh, S., S. K. Wong, Z. Jiang, B. Liu, Y. Wang, Q. Hao, V. Gorbunova, X. Liu, and Z. Zhou. 2018. Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice. eLife 7.

    Google Scholar 

  22. Kanfi, Y., S. Naiman, G. Amir, V. Peshti, G. Zinman, L. Nahum, Z. Bar-Joseph, and H.Y. Cohen. 2012. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483: 218–221.

    Article  CAS  Google Scholar 

  23. Sundaresan, N.R., P. Vasudevan, L. Zhong, G. Kim, S. Samant, V. Parekh, V.B. Pillai, P.V. Ravindra, M. Gupta, V. Jeevanandam, J.M. Cunningham, C.X. Deng, D.B. Lombard, R. Mostoslavsky, and M.P. Gupta. 2012. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nature Medicine 18: 1643–1650.

    Article  CAS  Google Scholar 

  24. Donehower, L.A., and G. Lozano. 2009. 20 years studying p53 functions in genetically engineered mice. Nature Reviews Cancer 9: 831–841.

    Article  CAS  Google Scholar 

  25. Donehower, L.A., M. Harvey, B.L. Slagle, M.J. McArthur, C.A. Montgomery Jr., J.S. Butel, and A. Bradley. 1992. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356: 215–221.

    Article  CAS  Google Scholar 

  26. Tyner, S.D., S. Venkatachalam, J. Choi, S. Jones, N. Ghebranious, H. Igelmann, X. Lu, G. Soron, B. Cooper, C. Brayton, S.H. Park, T. Thompson, G. Karsenty, A. Bradley, and L.A. Donehower. 2002. p53 mutant mice that display early ageing-associated phenotypes. Nature 415: 45–53.

    Article  CAS  Google Scholar 

  27. Langley, E., M. Pearson, M. Faretta, U.M. Bauer, R.A. Frye, S. Minucci, P.G. Pelicci, and T. Kouzarides. 2002. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO Journal 21: 2383–2396.

    Article  CAS  Google Scholar 

  28. Kamel, C., M. Abrol, K. Jardine, X. He, and M.W. McBurney. 2006. SirT1 fails to affect p53-mediated biological functions. Aging Cell 5: 81–88.

    Article  CAS  Google Scholar 

  29. Culmsee, C., X. Zhu, Q.S. Yu, S.L. Chan, S. Camandola, Z. Guo, N.H. Greig, and M.P. Mattson. 2001. A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide. Journal of Neurochemistry 77: 220–228.

    Article  CAS  Google Scholar 

  30. Zhu, X., Q.S. Yu, R.G. Cutler, C.W. Culmsee, H.W. Holloway, D.K. Lahiri, M.P. Mattson, and N.H. Greig. 2002. Novel p53 inactivators with neuroprotective action: syntheses and pharmacological evaluation of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole derivatives. Journal of Medicinal Chemistry 45: 5090–5097.

    Article  CAS  Google Scholar 

  31. Duan, W., X. Zhu, B. Ladenheim, Q.S. Yu, Z. Guo, J. Oyler, R.G. Cutler, J.L. Cadet, N.H. Greig, and M.P. Mattson. 2002. p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism. Annals of Neurology 52: 597–606.

    Article  CAS  Google Scholar 

  32. Thirumurthi, U., J. Shen, W. Xia, A.M. LaBaff, Y. Wei, C.W. Li, W.C. Chang, C.H. Chen, H.K. Lin, D. Yu, and M.C. Hung. 2014. MDM2-mediated degradation of SIRT6 phosphorylated by AKT1 promotes tumorigenesis and trastuzumab resistance in breast cancer. Sci Signal, 7: ra71.

    Article  Google Scholar 

  33. Van Meter, M., M. Simon, G. Tombline, A. May, T.D. Morello, B.P. Hubbard, K. Bredbenner, R. Park, D.A. Sinclair, V.A. Bohr, V. Gorbunova, and A. Seluanov. 2016. JNK Phosphorylates SIRT6 to stimulate DNA double-strand break repair in response to oxidative stress by recruiting PARP1 to DNA breaks. Cell Reports 16: 2641–2650.

    Article  Google Scholar 

  34. Hu, S., H. Liu, Y. Ha, X. Luo, M. Motamedi, M.P. Gupta, J.X. Ma, R.G. Tilton, and W. Zhang. 2015. Posttranslational modification of Sirt6 activity by peroxynitrite. Free Radical Biology and Medicine 79: 176–185.

    Article  CAS  Google Scholar 

  35. Cai, J., Y. Zuo, T. Wang, Y. Cao, R. Cai, F.L. Chen, J. Cheng, and J. Mu. 2016. A crucial role of SUMOylation in modulating Sirt6 deacetylation of H3 at lysine 56 and its tumor suppressive activity. Oncogene 35: 4949–4956.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dana-Farber Cancer Institute, Boston, MA, USA

    Dr. Shrestha Ghosh

Authors
  1. Dr. Shrestha Ghosh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shrestha Ghosh .

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ghosh, S. (2019). Discussion. In: SIRT6 Activities in DNA Damage Repair and Premature Aging. Springer Theses. Springer, Singapore. https://doi.org/10.1007/978-981-32-9267-3_6

Download citation

Publish with us

Policies and ethics

Search

Navigation