Regulation of TP53 Activity through Acetylation

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R-HSA-6804758
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Pathway
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Homo sapiens
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Transcriptional activity of TP53 is positively regulated by acetylation of several of its lysine residues. BRD7 binds TP53 and promotes acetylation of TP53 lysine residue K382 by acetyltransferase EP300 (p300). Acetylation of K382 enhances TP53 binding to target promoters, including CDKN1A (p21), MDM2, SERPINE1, TIGAR, TNFRSF10C and NDRG1 (Bensaad et al. 2010, Burrows et al. 2010. Drost et al. 2010). The histone acetyltransferase KAT6A, in the presence of PML, also acetylates TP53 at K382, and, in addition, acetylates K120 of TP53. KAT6A-mediated acetylation increases transcriptional activation of CDKN1A by TP53 (Rokudai et al. 2013). Acetylation of K382 can be reversed by the action of the NuRD complex, containing the TP53-binding MTA2 subunit, resulting in inhibition of TP53 transcriptional activity (Luo et al. 2000). Acetylation of lysine K120 in the DNA binding domain of TP53 by the MYST family acetyltransferases KAT8 (hMOF) and KAT5 (TIP60) can modulate the decision between cell cycle arrest and apoptosis (Sykes et al. 2006, Tang et al. 2006). Studies with acetylation-defective knock-in mutant mice indicate that lysine acetylation in the p53 DNA binding domain acts in part by uncoupling transactivation and transrepression of gene targets, while retaining ability to modulate energy metabolism and production of reactive oxygen species (ROS) and influencing ferroptosis (Li et al. 2012, Jiang et al. 2015).

Literature References
PubMed ID Title Journal Year
16839880 TIGAR, a p53-inducible regulator of glycolysis and apoptosis

Bensaad, K, Tsuruta, A, Selak, MA, Vidal, MN, Nakano, K, Bartrons, R, Gottlieb, E, Vousden, KH

Cell 2006
23431171 MOZ increases p53 acetylation and premature senescence through its complex formation with PML

Rokudai, S, Laptenko, O, Arnal, SM, Taya, Y, Kitabayashi, I, Prives, C

Proc. Natl. Acad. Sci. U.S.A. 2013
22682249 Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence

Li, T, Kon, N, Jiang, L, Tan, M, Ludwig, T, Zhao, Y, Baer, R, Gu, W

Cell 2012
20228809 BRD7 is a candidate tumour suppressor gene required for p53 function

Drost, J, Mantovani, F, Tocco, F, Elkon, R, Comel, A, Holstege, H, Kerkhoven, R, Jonkers, J, Voorhoeve, PM, Agami, R, Del Sal, G

Nat. Cell Biol. 2010
17189186 Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis

Tang, Y, Luo, J, Zhang, W, Gu, W

Mol. Cell 2006
11099047 Deacetylation of p53 modulates its effect on cell growth and apoptosis

Luo, J, Su, F, Chen, D, Shiloh, A, Gu, W

Nature 2000
25799988 Ferroptosis as a p53-mediated activity during tumour suppression

Jiang, L, Kon, N, Li, T, Wang, SJ, Su, T, Hibshoosh, H, Baer, R, Gu, W

Nature 2015
20660729 Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence

Burrows, AE, Smogorzewska, A, Elledge, SJ

Proc. Natl. Acad. Sci. U.S.A. 2010
17189187 Acetylation of the p53 DNA-binding domain regulates apoptosis induction

Sykes, SM, Mellert, HS, Holbert, MA, Li, K, Marmorstein, R, Lane, WS, McMahon, SB

Mol. Cell 2006
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