Skip to main content
SpringerLink
Log in

Results-II. Haploinsufficiency of p53 Rescues Lifespan and Premature Aging-Associated Abnormalities in Sirt6-Deficient Mice

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

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

  • 262 Accesses

Abstract

This chapter highlights the interplay between SIRT6 and p53, establishing p53 as a novel substrate for SIRT6-mediated deacetylation. It also illustrates upregulated p53 signaling as an underlying cause of premature mortality of SIRT6-deficient mice by the age of 4 weeks. This claim is further substantiated by the rescued lifespan and several other senescence-associated phenotypes in Sirt6-deficient mice by haploinsufficiency of p53 (Ghosh et al. in Elife 7:e32127, 2016 [1]).

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. 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: e32127.

    Article  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. 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 

  4. 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 

  5. 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 

  6. Kugel, S., and R. Mostoslavsky. 2014. Chromatin and beyond: the multitasking roles for SIRT6. Trends in Biochemical Sciences 39: 72–81.

    Article  CAS  Google Scholar 

  7. 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 Reviews.

    Google Scholar 

  8. Vousden, K.H., and C. Prives. 2009. Blinded by the light: The growing complexity of p53. Cell 137: 413–431.

    Article  CAS  Google Scholar 

  9. Gu, W., and R.G. Roeder. 1997. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90: 595–606.

    Article  CAS  Google Scholar 

  10. Brooks, C.L., and W. Gu. 2011. The impact of acetylation and deacetylation on the p53 pathway. Protein and Cell 2: 456–462.

    Article  CAS  Google Scholar 

  11. Gu, B., and W.G. Zhu. 2012. Surf the post-translational modification network of p53 regulation. International Journal of Biological Sciences 8: 672–684.

    Article  Google Scholar 

  12. 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 USA 111: 10684–10689.

    Article  CAS  Google Scholar 

  13. 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 

  14. Varela, I., J. Cadinanos, A.M. Pendas, A. Gutierrez-Fernandez, A.R. Folgueras, L.M. Sanchez, Z. Zhou, F.J. Rodriguez, C.L. Stewart, J.A. Vega, K. Tryggvason, J.M. Freije, and C. Lopez-Otin. 2005. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Nature 437: 564–568.

    Article  CAS  Google Scholar 

  15. Michishita, E., J.Y. Park, J.M. Burneskis, J.C. Barrett, and I. Horikawa. 2005. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Molecular Biology of the Cell 16: 4623–4635.

    Article  CAS  Google Scholar 

  16. 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 

  17. Kruse, J.P., and W. Gu. 2009. Modes of p53 regulation. Cell 137: 609–622.

    Article  CAS  Google Scholar 

  18. Reed, S.M., and D.E. Quelle. 2014. p53 Acetylation: Regulation and Consequences. Cancers (Basel) 7: 30–69.

    Article  Google Scholar 

  19. Loughery, J., M. Cox, L.M. Smith, and D.W. Meek. 2014. Critical role for p53-serine 15 phosphorylation in stimulating transactivation at p53-responsive promoters. Nucleic Acids Research 42: 7666–7680.

    Article  CAS  Google Scholar 

  20. Kaidi, A., B.T. Weinert, C. Choudhary, and S.P. Jackson. 2010. Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science 329: 1348–1353.

    Article  CAS  Google Scholar 

  21. Appella, E., and C.W. Anderson. 2000. Signaling to p53: Breaking the posttranslational modification code. Pathologie Biologie 48: 227–245.

    CAS  PubMed  Google Scholar 

  22. Marouco, D., A.V. Garabadgiu, G. Melino, and N.A. Barlev. 2013. Lysine-specific modifications of p53: A matter of life and death? Oncotarget 4: 1556–1571.

    Article  Google Scholar 

  23. 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 

  24. Jacks, T., L. Remington, B.O. Williams, E.M. Schmitt, S. Halachmi, R.T. Bronson, and R.A. Weinberg. 1994. Tumor spectrum analysis in p53-mutant mice. Current Biology 4: 1–7.

    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. Silberman, D.M., K. Ross, P.H. Sande, S. Kubota, S. Ramaswamy, R.S. Apte, and R. Mostoslavsky. 2014. SIRT6 is required for normal retinal function. PLoS ONE 9: e98831.

    Article  Google Scholar 

  28. Brochier, C., G. Dennis, M.A. Rivieccio, K. McLaughlin, G. Coppola, R.R. Ratan, and B. Langley. 2013. Specific acetylation of p53 by HDAC inhibition prevents DNA damage-induced apoptosis in neurons. Journal of Neuroscience 33: 8621–8632.

    Article  CAS  Google Scholar 

  29. Lopez-Otin, C., M.A. Blasco, L. Partridge, M. Serrano, and G. Kroemer. 2013. The hallmarks of aging. Cell 153: 1194–1217.

    Article  CAS  Google Scholar 

  30. Li, J., X. Liu, B. Zuo, and L. Zhang. 2016. The role of bone marrow microenvironment in governing the balance between osteoblastogenesis and adipogenesis. Aging and Disease 7: 514–525.

    Article  Google Scholar 

  31. Amir, H., T. Touboul, K. Sabatini, D. Chhabra, I. Garitaonandia, J.F. Loring, R. Morey, and L.C. Laurent. 2016. Spontaneous single-copy loss of TP53 in human embryonic stem cells markedly increases cell proliferation and survival. Stem Cells.

    Google Scholar 

  32. Belle, J.I., D. Langlais, J.C. Petrov, M. Pardo, R.G. Jones, P. Gros, and A. Nijnik. 2015. p53 mediates loss of hematopoietic stem cell function and lymphopenia in Mysm1 deficiency. Blood 125: 2344–2348.

    Article  CAS  Google Scholar 

  33. Lu, X., Y. Wei, and F. Liu. 2015. Direct regulation of p53 by miR-142a-3p mediates the survival of hematopoietic stem and progenitor cells in zebrafish. Cell Discovery 1: 15027.

    Article  CAS  Google Scholar 

  34. Pan, H., D. Guan, X. Liu, J. Li, L. Wang, J. Wu, J. Zhou, W. Zhang, R. Ren, W. Zhang, Y. Li, J. Yang, Y. Hao, T. Yuan, G. Yuan, H. Wang, Z. Ju, Z. Mao, J. Li, J. Qu, F. Tang, and G.H. Liu. 2016. SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Research 26: 190–205.

    Article  CAS  Google Scholar 

  35. Ghosh, S., Liu, B., Wang, Y., Hao, Q., and Zhou, Z. 2015. Lamin A Is an Endogenous SIRT6 Activator and Promotes SIRT6-Mediated DNA Repair. Cell Reports 13 (7): 1396–1406.

    Article  CAS  Google Scholar 

  36. 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 

  37. 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 

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). Results-II. Haploinsufficiency of p53 Rescues Lifespan and Premature Aging-Associated Abnormalities in Sirt6-Deficient Mice. In: SIRT6 Activities in DNA Damage Repair and Premature Aging. Springer Theses. Springer, Singapore. https://doi.org/10.1007/978-981-32-9267-3_4

Download citation

Publish with us

Policies and ethics

Search

Navigation