Functional analysis of the acetylation of human p53 in DNA damage responses
Received date: 09 Feb 2014
Accepted date: 24 Feb 2014
Published date: 31 Jul 2014
Copyright
As a critical tumor suppressor, p53 is inactivated in human cancer cells by somatic gene mutation or disruption of pathways required for its activation. Therefore, it is critical to elucidate the mechanism underlying p53 activation after genotoxic and cellular stresses. Accumulating evidence has indicated the importance of posttranslational modifications such as acetylation in regulating p53 stability and activity. However, the physiological roles of the eight identified acetylation events in regulating p53 responses remain to be fully understood. By employing homologous recombination, we introduced various combinations of missense mutations (lysine to arginine) into eight acetylation sites of the endogenous p53 gene in human embryonic stem cells (hESCs). By determining the p53 responses to DNA damage in the p53 knock-in mutant hESCs and their derivatives, we demonstrate physiological importance of the acetylation events within the core domain (K120 and K164) and at the C-terminus (K370/372/373/381/382/ 386) in regulating human p53 responses to DNA damage.
Sun-Ku Chung , Shengyun Zhu , Yang Xu , Xuemei Fu . Functional analysis of the acetylation of human p53 in DNA damage responses[J]. Protein & Cell, 2014 , 5(7) : 544 -551 . DOI: 10.1007/s13238-014-0048-x
| 1 |
Brooks C, Gu W (2011) The impact of acetylation and deacetylation on the p53 pathway. Protein Cell2: 456-462
|
| 2 |
Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell120: 513-522
|
| 3 |
Chao C, Hergenhahn M, Kaeser MD, Wu Z, Saito S, Iggo R, Hollstein M, Appella E, Xu Y (2003) Cell type and promoterspecific roles of Ser18 phosphorylation in regulating p53 responses. J Biol Chem278: 41028-41033
|
| 4 |
Chao C, Herr D, Chun J, Xu Y (2006) Ser18 and 23 phosphorylation is required for p53-dependent apoptosis and tumor suppression. Embo J25: 2615-2622 Epub 2006 Jun 2611
|
| 5 |
Cowan CA, Klimanskaya I, McMahon J, Atienza J, Witmyer J, Zucker JP, Wang S, Morton CC, McMahon AP, Powers D
|
| 6 |
Feng L, Lin T, Uranishi H, Gu W, Xu Y (2005) Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity. Mol Cell Biol25: 5389-5395
|
| 7 |
Li T, Kon N, Jiang L, Tan M, Ludwig T, Zhao Y, Baer R, Gu W (2012) Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell149: 1269-1283
|
| 8 |
Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, Xu Y (2005) p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. Nat Cell Biol7: 165-171 Epub 2004 Dec 26
|
| 9 |
Liu D, Ou L, Clemenson GD, Chao C, Lutske ME, Zambetti GP, Gage FH, Xu Y (2010) Puma is required for p53-induced depletion of adult stem cells. Nat Cell Biol12: 993-998
|
| 10 |
Song H, Chung S-K, Xu Y (2010) Modeling disease in human ESCs using an efficient BAC-based homologous recombination system. Cell Stem Cell6: 80-89
|
| 11 |
Sykes SM, Mellert HS, Holbert MA, Li K, Marmorstein R, Lane WS, McMahon SB (2006) Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol Cell24: 841-851
|
| 12 |
Tang Y, Luo J, Zhang W, Gu W (2006) Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol Cell24: 827-839
|
| 13 |
Tang Y, Zhao W, Chen Y, Zhao Y, Gu W (2008) Acetylation is indispensable for p53 activation. Cell133: 612-626
|
| 14 |
Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell137: 413-431
|
| 15 |
Zhang Z-N, Chung S-K, Xu Z, Xu Y (2014) Oct4 maintains the pluripotency of human embryonic stem cells by inactivating p53 through Sirt1-mediated deacetylation. Stem Cells32: 157-165
|
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