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).
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Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, Baer R, Gu W.; ''Ferroptosis as a p53-mediated activity during tumour suppression.''; PubMedEurope PMCScholia
Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH.; ''TIGAR, a p53-inducible regulator of glycolysis and apoptosis.''; PubMedEurope PMCScholia
Rokudai S, Laptenko O, Arnal SM, Taya Y, Kitabayashi I, Prives C.; ''MOZ increases p53 acetylation and premature senescence through its complex formation with PML.''; PubMedEurope PMCScholia
Zhang Y, LeRoy G, Seelig HP, Lane WS, Reinberg D.; ''The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities.''; PubMedEurope PMCScholia
Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D.; ''Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation.''; PubMedEurope PMCScholia
Luo J, Su F, Chen D, Shiloh A, Gu W.; ''Deacetylation of p53 modulates its effect on cell growth and apoptosis.''; PubMedEurope PMCScholia
Keune WJ, Jones DR, Bultsma Y, Sommer L, Zhou XZ, Lu KP, Divecha N.; ''Regulation of phosphatidylinositol-5-phosphate signaling by Pin1 determines sensitivity to oxidative stress.''; PubMedEurope PMCScholia
Zou J, Marjanovic J, Kisseleva MV, Wilson M, Majerus PW.; ''Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis.''; PubMedEurope PMCScholia
Jones DR, Bultsma Y, Keune WJ, Halstead JR, Elouarrat D, Mohammed S, Heck AJ, D'Santos CS, Divecha N.; ''Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kbeta.''; PubMedEurope PMCScholia
Clarke JH, Irvine RF.; ''Evolutionarily conserved structural changes in phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) isoforms are responsible for differences in enzyme activity and localization.''; PubMedEurope PMCScholia
Drost J, Mantovani F, Tocco F, Elkon R, Comel A, Holstege H, Kerkhoven R, Jonkers J, Voorhoeve PM, Agami R, Del Sal G.; ''BRD7 is a candidate tumour suppressor gene required for p53 function.''; PubMedEurope PMCScholia
Li T, Kon N, Jiang L, Tan M, Ludwig T, Zhao Y, Baer R, Gu W.; ''Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence.''; PubMedEurope PMCScholia
Burrows AE, Smogorzewska A, Elledge SJ.; ''Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence.''; PubMedEurope PMCScholia
Ciruela A, Hinchliffe KA, Divecha N, Irvine RF.; ''Nuclear targeting of the beta isoform of type II phosphatidylinositol phosphate kinase (phosphatidylinositol 5-phosphate 4-kinase) by its alpha-helix 7.''; PubMedEurope PMCScholia
Sykes SM, Mellert HS, Holbert MA, Li K, Marmorstein R, Lane WS, McMahon SB.; ''Acetylation of the p53 DNA-binding domain regulates apoptosis induction.''; PubMedEurope PMCScholia
Bultsma Y, Keune WJ, Divecha N.; ''PIP4Kbeta interacts with and modulates nuclear localization of the high-activity PtdIns5P-4-kinase isoform PIP4Kalpha.''; PubMedEurope PMCScholia
Pedeux R, Sengupta S, Shen JC, Demidov ON, Saito S, Onogi H, Kumamoto K, Wincovitch S, Garfield SH, McMenamin M, Nagashima M, Grossman SR, Appella E, Harris CC.; ''ING2 regulates the onset of replicative senescence by induction of p300-dependent p53 acetylation.''; PubMedEurope PMCScholia
Tang Y, Luo J, Zhang W, Gu W.; ''Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis.''; PubMedEurope PMCScholia
Gozani O, Karuman P, Jones DR, Ivanov D, Cha J, Lugovskoy AA, Baird CL, Zhu H, Field SJ, Lessnick SL, Villasenor J, Mehrotra B, Chen J, Rao VR, Brugge JS, Ferguson CG, Payrastre B, Myszka DG, Cantley LC, Wagner G, Divecha N, Prestwich GD, Yuan J.; ''The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor.''; PubMedEurope PMCScholia
The N-terminal region of BRD7, upstream of its bromodomain that is responsible for interaction with chromatin, binds the C-terminus of TP53 (p53) (Drost et al. 2010, Burrows et al. 2010). BRD7 also binds and can recruit EP300 (p300) to TP53 target promoters CDKN1A and MDM2 (Drost et al. 2010). BRD7 positively regulates transcription of other TP53 targets: SERPINE1, TIGAR (Bensaad et al. 2006), TNFRSF10C and NDGR1, presumably via a similar mechanism as in the case of CDKN1A and MDM2 (Drost et al. 2010, Burrows et al. 2010).
BRD7 promotes EP300 (p300)-mediated acetylation of TP53 on lysine residue K382, which enhances binding of TP53 to its target promoters. Also, BRD7 induces EP300-mediated acetylation of histone 3 on lysine residue K10 (also labeled in literature as K9), creating the H3K9 active chromatin mark at CDKN1A and MDM2 promoters (Drost et al. 2010), and possibly other TP53 promoters co-regulated by BRD7, such as SERPINE1, TIGAR, TNFRSF10C and NDRG1.
The histone acetyltransferase KAT6A, which functions as part of the MOZ/MORF complex (Ullah et al. 2008), associates with TP53 (p53) and PML (Rokudai et al. 2013). KAT6A can independently associate with TP53 and PML, but the presence of PML enhances KAT6A-mediated acetylation of TP53. Phosphorylation of KAT6A by activated AKT inhibits PML binding (Rokudai et al. 2013).
KAT6A histone acetyltransferase, part of the MOZ/MORF complex, acetylates TP53 (p53) on lysine residues K120 and K382. The acetylation of TP53 by KAT6A is enhanced in the presence of PML and results in increased transcriptional activation of the CDKN1A (p21) gene by TP53 (Rokudai et al. 2013).
Activated AKT phosphorylates the histone acetyltransferase KAT6A on threonine residue T369, preventing association of PML with the KAT6A complex and repressing KAT6A-mediated acetylation of TP53 (p53) (Rokudai et al. 2013).
MTA2 (PID), a component of the NuRD complex, binds TP53 (p53) and thus targets histone deacetylases of the NuRD complex to TP53. The NuRD complex deacetylates the C-terminus of TP53, including acetylated lysine K382, thus inhibiting TP53 transcriptional activity (Luo et al. 2000).
The PHD finger of ING2 binds phosphatidylinositol-5-phosphate (PI5P) (Gozani et al. 2003), which promotes nuclear retention of ING2 (Jones et al. 2006, Zou et al. 2007).
Under conditions of cellular stress, TMEM55B (type I phosphatidylinositol 4,5-bisphosphate 4-phosphatase) translocates to the nucleus through an unknown mechanism (Zou et al. 2007).
Translocation of TMEM55B (type I phosphatidylinositol 4,5-bisphosphate 4-phosphatase) to the nucleus under conditions of cellular stress leads to dephosphorylation of nuclear PI(4,5)P2 to PI5P, thus increasing the concentration of PI5P in the nucleus (Zou et al. 2007). PIP2 and its derivatives are not associated with nuclear envelope structures (Bornenkov et al. 1998) but localize to poorly defined subnuclear compartments called nuclear specks (reviewed by Barlow et al. 2010).
The histone acetyltransferase EP300 (p300), recruited to TP53 (p53) by ING2, acetylates TP53 on lysine residue K382, which may contribute to TP53-dependent apoptosis (Padeux et al. 2005). PI5P positively regulates TP53 acetylation (Zou et al. 2007), possibly by increasing the amount of ING2 in the nucleus (Gozani et al. 2003).
In the nucleus, phosphatidylinositol 5-phosphate (PI5P) is phosphorylated to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) mainly by phosphatidylinositol-5-phosphate 4-kinase type-2 beta (PIP4K2B). In the nucleus, PIP4K2B predominantly functions as a homodimer or a heterodimer with PIP4K2A. A low level of PIP4K2A homodimers can also be found in the nucleus. Nuclear localization of PIP4K2C has not been examined but is assumed to be possible, at least through formation of heterodimers with PIP4K2B (Ciruela et al. 2000, Jones et al. 2006, Bultsma et al. 2010). Under conditions of cellular stress, nuclear PIP4K2B can be phosphorylated by p38 MAP kinases, resulting in PIP4K2B inactivation. The putative p38 target site, serine residue S326 of PIP4K2B, is conserved in PIP4K2A, but the role and mechanism of p38-mediated regulation of PIP4K2 isoforms has not been studied in detail (Jones et al. 2006).
Under conditions of cellular stress, such as increased level of reactive oxygen species, MAP2K6 (MKK6), and possibly other kinases of the p38 MAPK family, phosphorylates PIP4K2B at serine residue S326. Threonine residue T322 of PIP4K2B is also phosphorylated under stress conditions, but the responsible kinase is not known. MAP2K6 may also phosphorylate PIP4K2A, but not PIP4K2C (Kuene et al. 2012).
Peptidyl-prolyl cis-trans isomerase PIN1 binds to PIP4K2B phosphorylated at serine residue S326. PIP4K2B is phosphorylated at S326 under conditions of cellular stress, such as increased level of reactive oxygen species (ROS). Phosphorylation of PIP4K2B at threonine residue T322 may also contribute to PIN1 binding. PIN1 induces conformational change of PIP4K2B, resulting in inactivation of PIP4K2B dimers. This enables increase of the nuclear PI5P levels. PI5P positively regulates expression of genes involved in neutralization of ROS (Keune et al. 2012).
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