Reactome | Regulation of TP53 Activity through Acetylation

Regulation of TP53 Activity through Acetylation

Stable Identifier

R-HSA-6804758

Type

Pathway

Species

Homo sapiens

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Regulation of TP53 Activity through Acetylation

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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