Protein & Cell

, Volume 2, Issue 6, pp 456–462 | Cite as

The impact of acetylation and deacetylation on the p53 pathway



The p53 tumor suppressor is a sequence-specific transcription factor that undergoes an abundance of post-translational modifications for its regulation and activation. Acetylation of p53 is an important reversible enzymatic process that occurs in response to DNA damage and genotoxic stress and is indispensible for p53 transcriptional activity. p53 was the first non-histone protein shown to be acetylated by histone acetyl transferases, and a number of more recent in vivo models have underscored the importance of this type of modification for p53 activity. Here, we review the current knowledge and recent findings of p53 acetylation and deacetylation and discuss the implications of these processes for the p53 pathway.


p53 Mdm2 acetylation deacetylation destabilization ubiquitination transcriptional activation and stability 


  1. Appella, E., and Anderson, C.W. (2001). Post-translational modifications and activation of p53 by genotoxic stresses. Eur J Biochem 268, 2764–2772.CrossRefGoogle Scholar
  2. Barlev, N.A., Liu, L., Chehab, N.H., Mansfield, K., Harris, K.G., Halazonetis, T.D., and Berger, S.L. (2001). Acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases. Mol Cell 8, 1243–1254.CrossRefGoogle Scholar
  3. Benkirane, M., Sardet, C., and Coux, O. (2010). Lessons from interconnected ubiquitylation and acetylation of p53: think metastable networks. Biochem Soc Trans 38, 98–103.CrossRefGoogle Scholar
  4. Bordone, L., and Guarente, L. (2005). Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 6, 298–305.CrossRefGoogle Scholar
  5. Brooks, C.L., and Gu, W. (2006). p53 ubiquitination: Mdm2 and beyond. Mol Cell 21, 307–315.CrossRefGoogle Scholar
  6. Chao, C., Wu, Z., Mazur, S.J., Borges, H., Rossi, M., Lin, T., Wang, J. Y., Anderson, C.W., Appella, E., and Xu, Y. (2006). Acetylation of mouse p53 at lysine 317 negatively regulates p53 apoptotic activities after DNA damage. Mol Cell Biol 26, 6859–6869.CrossRefGoogle Scholar
  7. Chen, D., Kon, N., Li, M., Zhang, W., Qin, J., and Gu, W. (2005). ARFBP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 121, 1071–1083.CrossRefGoogle Scholar
  8. Cheng, H.L., Mostoslavsky, R., Saito, S., Manis, J.P., Gu, Y., Patel, P., Bronson, R., Appella, E., Alt, F.W., and Chua, K.F. (2003). Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci U S A 100, 10794–10799.CrossRefGoogle Scholar
  9. Choudhary, C., Kumar, C., Gnad, F., Nielsen, M.L., Rehman, M., Walther, T.C., Olsen, J.V., and Mann, M. (2009). Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840.CrossRefGoogle Scholar
  10. Chua, K.F., Mostoslavsky, R., Lombard, D.B., Pang, W.W., Saito, S., Franco, S., Kaushal, D., Cheng, H.L., Fischer, M.R., Stokes, N., et al. (2005). Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab 2, 67–76.CrossRefGoogle Scholar
  11. de Ruijter, A.J., van Gennip, A.H., Caron, H.N., Kemp, S., and van Kuilenburg, A.B. (2003). Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370, 737–749.CrossRefGoogle Scholar
  12. Dornan, D., Wertz, I., Shimizu, H., Arnott, D., Frantz, G.D., Dowd, P., O’Rourke, K., Koeppen, H., and Dixit, V.M. (2004). The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 429, 86–92.CrossRefGoogle Scholar
  13. Fan, W., and Luo, J. (2010). SIRT1 regulates UV-induced DNA repair through deacetylating XPA. Mol Cell 39, 247–258.CrossRefGoogle Scholar
  14. Feng, L., Lin, T., Uranishi, H., Gu, W., and Xu, Y. (2005). Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity. Mol Cell Biol 25, 5389–5395.CrossRefGoogle Scholar
  15. Goodman, R.H., and Smolik, S. (2000). CBP/p300 in cell growth, transformation, and development. Genes Dev 14, 1553–1577.Google Scholar
  16. Grossman, S.R., Deato, M.E., Brignone, C., Chan, H.M., Kung, A.L., Tagami, H., Nakatani, Y., and Livingston, D.M. (2003). Polyubiquitination of p53 by a ubiquitin ligase activity of p300. Science 300, 342–344.CrossRefGoogle Scholar
  17. Gu, W., and Roeder, R.G. (1997). Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606.CrossRefGoogle Scholar
  18. Harbison, C.T., Gordon, D.B., Lee, T.I., Rinaldi, N.J., Macisaac, K.D., Danford, T.W., Hannett, N.M., Tagne, J.B., Reynolds, D.B., Yoo, J., et al. (2004). Transcriptional regulatory code of a eukaryotic genome. Nature 431, 99–104.CrossRefGoogle Scholar
  19. Huang, J., Gan, Q., Han, L., Li, J., Zhang, H., Sun, Y., Zhang, Z., and Tong, T. (2008). SIRT1 overexpression antagonizes cellular senescence with activated ERK/S6k1 signaling in human diploid fibroblasts. PLoS One 3, e1710.CrossRefGoogle Scholar
  20. Itahana, K., Mao, H., Jin, A., Itahana, Y., Clegg, H.V., Lindström, M.S., Bhat, K.P., Godfrey, V.L., Evan, G.I., and Zhang, Y. (2007). Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell 12, 355–366.CrossRefGoogle Scholar
  21. Ito, A., Lai, C.H., Zhao, X., Saito, S., Hamilton, M.H., Appella, E., and Yao, T.P. (2001). p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J 20, 1331–1340.CrossRefGoogle Scholar
  22. Iyer, N.G., Ozdag, H., and Caldas, C. (2004). p300/CBP and cancer. Oncogene 23, 4225–4231.CrossRefGoogle Scholar
  23. Jones, S.N., Roe, A.E., Donehower, L.A., and Bradley, A. (1995). Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378, 206–208.CrossRefGoogle Scholar
  24. Joo, W.S., Jeffrey, P.D., Cantor, S.B., Finnin, M.S., Livingston, D.M., and Pavletich, N.P. (2002). Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure. Genes Dev 16, 583–593.CrossRefGoogle Scholar
  25. Kim, J.E., Chen, J., and Lou, Z. (2008). DBC1 is a negative regulator of SIRT1. Nature 451, 583–586.CrossRefGoogle Scholar
  26. Kim, S.C., Sprung, R., Chen, Y., Xu, Y., Ball, H., Pei, J., Cheng, T., Kho, Y., Xiao, H., Xiao, L., et al. (2006). Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell 23, 607–618.CrossRefGoogle Scholar
  27. Knights, C.D., Catania, J., Di Giovanni, S., Muratoglu, S., Perez, R., Swartzbeck, A., Quong, A.A., Zhang, X., Beerman, T., Pestell, R. G., et al. (2006). Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate. J Cell Biol 173, 533–544.CrossRefGoogle Scholar
  28. Krummel, K.A., Lee, C.J., Toledo, F., and Wahl, G.M. (2005). The Cterminal lysines fine-tune P53 stress responses in a mouse model but are not required for stability control or transactivation. Proc Natl Acad Sci U S A 102, 10188–10193.CrossRefGoogle Scholar
  29. Kruse, J.P., and Gu, W. (2009a). Modes of p53 regulation. Cell 137, 609–622.CrossRefGoogle Scholar
  30. Kruse, J.P., and Gu, W. (2009b). MSL2 promotes Mdm2-independent cytoplasmic localization of p53. J Biol Chem 284, 3250–3263.CrossRefGoogle Scholar
  31. Leng, R.P., Lin, Y., Ma, W., Wu, H., Lemmers, B., Chung, S., Parant, J. M., Lozano, G., Hakem, R., and Benchimol, S. (2003). Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 112, 779–791.CrossRefGoogle Scholar
  32. Levine, A.J., and Oren, M. (2009). The first 30 years of p53: growing ever more complex. Nat Rev Cancer 9, 749–758.CrossRefGoogle Scholar
  33. Li, A.G., Piluso, L.G., Cai, X., Gadd, B.J., Ladurner, A.G., and Liu, X. (2007). An acetylation switch in p53 mediates holo-TFIID recruitment. Mol Cell 28, 408–421.CrossRefGoogle Scholar
  34. Li, K., Casta, A., Wang, R., Lozada, E., Fan, W., Kane, S., Ge, Q., Gu, W., Orren, D., and Luo, J. (2008). Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation. J Biol Chem 283, 7590–7598.CrossRefGoogle Scholar
  35. Li, M., Luo, J., Brooks, C.L., and Gu, W. (2002). Acetylation of p53 inhibits its ubiquitination by Mdm2. J Biol Chem 277, 50607–50611.CrossRefGoogle Scholar
  36. Liu, L., Scolnick, D.M., Trievel, R.C., Zhang, H.B., Marmorstein, R., Halazonetis, T.D., and Berger, S.L. (1999). p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage. Mol Cell Biol 19, 1202–1209.CrossRefGoogle Scholar
  37. Luo, J., Li, M., Tang, Y., Laszkowska, M., Roeder, R.G., and Gu, W. (2004). Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo. Proc Natl Acad Sci U S A 101, 2259–2264.CrossRefGoogle Scholar
  38. Luo, J., Nikolaev, A.Y., Imai, S., Chen, D., Su, F., Shiloh, A., Guarente, L., and Gu, W. (2001). Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107, 137–148.CrossRefGoogle Scholar
  39. Luo, J., Su, F., Chen, D., Shiloh, A., and Gu, W. (2000). Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature 408, 377–381.CrossRefGoogle Scholar
  40. MacDonald, V.E., and Howe, L.J. (2009). Histone acetylation: where to go and how to get there. Epigenetics 4, 139–143.CrossRefGoogle Scholar
  41. Mellert, H., Sykes, S.M., Murphy, M.E., and McMahon, S.B. (2007). The ARF/oncogene pathway activates p53 acetylation within the DNA binding domain. Cell Cycle 6, 1304–1306.CrossRefGoogle Scholar
  42. Montes de Oca Luna, R., Wagner, D.S., and Lozano, G. (1995). Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378, 203–206.CrossRefGoogle Scholar
  43. Ringshausen, I., O’shea, C.C., Finch, A.J., Swigart, L.B., and Evan, G.I. (2006). Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell 10, 501–514.CrossRefGoogle Scholar
  44. Rodriguez, M.S., Desterro, J.M., Lain, S., Lane, D.P., and Hay, R.T. (2000). Multiple C-terminal lysine residues target p53 for ubiquitin-proteasome-mediated degradation. Mol Cell Biol 20, 8458–8467.CrossRefGoogle Scholar
  45. Sakaguchi, K., Herrera, J.E., Saito, S., Miki, T., Bustin, M., Vassilev, A., Anderson, C.W., and Appella, E. (1998). DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev 12, 2831–2841.CrossRefGoogle Scholar
  46. Sharpless, N.E., and DePinho, R.A. (2004). Telomeres, stem cells, senescence, and cancer. J Clin Invest 113, 160–168.CrossRefGoogle Scholar
  47. Sherr, C.J. (2001). The INK4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol 2, 731–737.CrossRefGoogle Scholar
  48. Shi, D., Pop, M.S., Kulikov, R., Love, I.M., Kung, A.L., and Grossman, S.R. (2009). CBP and p300 are cytoplasmic E4 polyubiquitin ligases for p53. Proc Natl Acad Sci U S A 106, 16275–16280.CrossRefGoogle Scholar
  49. Shieh, S.Y., Ikeda, M., Taya, Y., and Prives, C. (1997). DNA damageinduced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91, 325–334.CrossRefGoogle Scholar
  50. Sullivan, A., and Lu, X. (2007). ASPP: a new family of oncogenes and tumour suppressor genes. Br J Cancer 96, 196–200.CrossRefGoogle Scholar
  51. Sykes, S.M., Mellert, H.S., Holbert, M.A., Li, K., Marmorstein, R., Lane, W.S., and McMahon, S.B. (2006). Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol Cell 24, 841–851.CrossRefGoogle Scholar
  52. Tang, Y., Luo, J., Zhang, W., and Gu, W. (2006). Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol Cell 24, 827–839.CrossRefGoogle Scholar
  53. Tang, Y., Zhao, W., Chen, Y., Zhao, Y., and Gu, W. (2008). Acetylation is indispensable for p53 activation. Cell 133, 612–626.CrossRefGoogle Scholar
  54. Tyner, S.D., Venkatachalam, S., Choi, J., Jones, S., Ghebranious, N., Igelmann, H., Lu, X., Soron, G., Cooper, B., Brayton, C., et al. (2002). p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53.CrossRefGoogle Scholar
  55. Vaziri, H., Dessain, S.K., Ng Eaton, E., Imai, S.I., Frye, R.A., Pandita, T.K., Guarente, L., and Weinberg, R.A. (2001). hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149–159.CrossRefGoogle Scholar
  56. Wang, R.H., Sengupta, K., Li, C., Kim, H.S., Cao, L., Xiao, C., Kim, S., Xu, X., Zheng, Y., Chilton, B., et al. (2008a). Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 14, 312–323.CrossRefGoogle Scholar
  57. Wang, X., Taplick, J., Geva, N., and Oren, M. (2004). Inhibition of p53 degradation by Mdm2 acetylation. FEBS Lett 561, 195–201.CrossRefGoogle Scholar
  58. Wang, Y.H., Tsay, Y.G., Tan, B.C., Lo, W.Y., and Lee, S.C. (2003). Identification and characterization of a novel p300-mediated p53 acetylation site, lysine 305. J Biol Chem 278, 25568–25576.CrossRefGoogle Scholar
  59. Wang, Z., Zang, C., Rosenfeld, J.A., Schones, D.E., Barski, A., Cuddapah, S., Cui, K., Roh, T.Y., Peng, W., Zhang, M.Q., et al. (2008b). Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet 40, 897–903.CrossRefGoogle Scholar
  60. Yuan, Z., Zhang, X., Sengupta, N., Lane, W.S., and Seto, E. (2007). SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Mol Cell 27, 149–162.CrossRefGoogle Scholar
  61. Zhao, W., Kruse, J.P., Tang, Y., Jung, S.Y., Qin, J., and Gu, W. (2008). Negative regulation of the deacetylase SIRT1 by DBC1. Nature 451, 587–590.CrossRefGoogle Scholar
  62. Zhao, Y., Lu, S., Wu, L., Chai, G., Wang, H., Chen, Y., Sun, J., Yu, Y., Zhou, W., Zheng, Q., et al. (2006). Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21(Waf1/Cip1). Mol Cell Biol 26, 2782–2790.CrossRefGoogle Scholar
  63. Zhong, Q., Gao, W., Du, F., and Wang, X. (2005). Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121, 1085–1095.CrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  1. 1.Stemline Therapeutics, Inc.New YorkUSA
  2. 2.Institute for Cancer Genetics, and Department of Pathology College of Physicians & SurgeonsColumbia UniversityNew YorkUSA

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