Editing P53 (section)

== Regulation ==
p53 acts as a cellular stress sensor. It is normally kept at low levels by being constantly marked for degradation by the [[E3 ubiquitin ligase]] protein [[MDM2]].<ref name="Bykove2018">{{cite journal | vauthors = Bykov VJ, Eriksson SE, Bianchi J, Wiman KG | title = Targeting mutant p53 for efficient cancer therapy | journal = Nature Reviews. Cancer | volume = 18 | issue = 2 | pages = 89–102 | date = February 2018 | pmid = 29242642 | doi = 10.1038/nrc.2017.109 | s2cid = 4552678 }}</ref> p53 is activated in response to myriad stressors – including [[DNA damage]] (induced by either [[Ultraviolet|UV]], [[Ionizing radiation|IR]], or chemical agents such as hydrogen peroxide), [[oxidative stress]],<ref name="pmid18445702">{{cite journal | vauthors = Han ES, Muller FL, Pérez VI, Qi W, Liang H, Xi L, Fu C, Doyle E, Hickey M, Cornell J, Epstein CJ, Roberts LJ, Van Remmen H, Richardson A | title = The in vivo gene expression signature of oxidative stress | journal = Physiological Genomics | volume = 34 | issue = 1 | pages = 112–126 | date = June 2008 | pmid = 18445702 | pmc = 2532791 | doi = 10.1152/physiolgenomics.00239.2007 }}</ref> [[osmotic shock]], ribonucleotide depletion, [[Viral pneumonia|viral lung infections]]<ref>{{cite journal | vauthors = Grajales-Reyes GE, Colonna M | title = Interferon responses in viral pneumonias | journal = Science | volume = 369 | issue = 6504 | pages = 626–627 | date = August 2020 | pmid = 32764056 | doi = 10.1126/science.abd2208 | bibcode = 2020Sci...369..626G }}</ref> and deregulated oncogene expression. This activation is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a [[conformational change]] forces p53 to be activated as a [[Transcriptional regulation|transcription regulator]] in these cells. The critical event leading to the activation of p53 is the phosphorylation of its [[N-terminus|N-terminal]] domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals. {{cn|date=November 2024}}

The [[protein kinases]] that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the [[MAPK]] family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases ([[Ataxia telangiectasia and Rad3 related|ATR]], [[Ataxia telangiectasia mutated|ATM]], [[Chk1|CHK1]] and [[Chk2|CHK2]], [[DNA-PKcs|DNA-PK]], CAK, [[TP53RK]]) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. [[Oncogene]]s also stimulate p53 activation, mediated by the protein [[p14ARF]]. {{cn|date=November 2024}}

In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called [[Mdm2]] (also called HDM2 in humans), binds to p53, preventing its action and transports it from the [[Cell nucleus|nucleus]] to the [[cytosol]]. Mdm2 also acts as an [[ubiquitin ligase]] and covalently attaches [[ubiquitin]] to p53 and thus marks p53 for degradation by the [[proteasome]]. However, ubiquitylation of p53 is reversible. On activation of p53, Mdm2 is also activated, setting up a [[feedback loop]]. p53 levels can show [[oscillation]]s (or repeated pulses) in response to certain stresses, and these pulses can be important in determining whether the cells survive the stress, or die.<ref>{{cite journal | vauthors = Purvis JE, Karhohs KW, Mock C, Batchelor E, Loewer A, Lahav G | title = p53 dynamics control cell fate | journal = Science | volume = 336 | issue = 6087 | pages = 1440–1444 | date = June 2012 | pmid = 22700930 | pmc = 4162876 | doi = 10.1126/science.1218351 | bibcode = 2012Sci...336.1440P }}</ref>

MI-63 binds to MDM2, reactivating p53 in situations where p53's function has become inhibited.<ref>{{cite journal | vauthors = Canner JA, Sobo M, Ball S, Hutzen B, DeAngelis S, Willis W, Studebaker AW, Ding K, Wang S, Yang D, Lin J | title = MI-63: a novel small-molecule inhibitor targets MDM2 and induces apoptosis in embryonal and alveolar rhabdomyosarcoma cells with wild-type p53 | journal = British Journal of Cancer | volume = 101 | issue = 5 | pages = 774–81 | date = September 2009 | pmid = 19707204 | pmc = 2736841 | doi = 10.1038/sj.bjc.6605199 }}</ref>

A ubiquitin specific protease, [[USP7]] (or [[USP7|HAUSP]]), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation via the [[Ubiquitination|ubiquitin ligase pathway]]. This is one means by which p53 is stabilized in response to oncogenic insults. [[USP42]] has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress.<ref>{{cite journal | vauthors = Hock AK, Vigneron AM, Carter S, Ludwig RL, Vousden KH | title = Regulation of p53 stability and function by the deubiquitinating enzyme USP42 | journal = The EMBO Journal | volume = 30 | issue = 24 | pages = 4921–30 | date = November 2011 | pmid = 22085928 | pmc = 3243628 | doi = 10.1038/emboj.2011.419 }}</ref>

Recent research has shown that HAUSP is mainly localized in the nucleus, though a fraction of it can be found in the cytoplasm and mitochondria. Overexpression of HAUSP results in p53 stabilization. However, depletion of HAUSP does not result in a decrease in p53 levels but rather increases p53 levels due to the fact that HAUSP binds and deubiquitinates Mdm2. It has been shown that HAUSP is a better binding partner to Mdm2 than p53 in unstressed cells.

[[USP10]], however, has been shown to be located in the cytoplasm in unstressed cells and deubiquitinates cytoplasmic p53, reversing Mdm2 ubiquitination. Following DNA damage, USP10 translocates to the nucleus and contributes to p53 stability. Also USP10 does not interact with Mdm2.<ref name="pmid20096447" />

Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of transcriptional coactivators, like [[EP300|p300]] and [[PCAF]], which then acetylate the [[C-terminus|C-terminal]] end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as [[Sirt1]] and [[Sirt7]], can deacetylate p53, leading to an inhibition of apoptosis.<ref name="pmid18239138">{{cite journal | vauthors = Vakhrusheva O, Smolka C, Gajawada P, Kostin S, Boettger T, Kubin T, Braun T, Bober E | title = Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice | journal = Circulation Research | volume = 102 | issue = 6 | pages = 703–10 | date = March 2008 | pmid = 18239138 | doi = 10.1161/CIRCRESAHA.107.164558 | doi-access = free }}</ref> Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity. {{cn|date=November 2024}}

Epigenetic marks like histone methylation can also regulate p53, for example, p53 interacts directly with a repressive Trim24 cofactor that binds histones in regions of the genome that are epigenetically repressed.<ref name="pmid37386214">{{cite journal | vauthors = Isbel L, Iskar M, Durdu S, Grand RS, Weiss J, Hietter-Pfeiffer E, Kozicka Z, Michael AK, Burger L, Thomä NH, Schübeler D | title = Readout of histone methylation by Trim24 locally restricts chromatin opening by p53 | journal = Nature Structural & Molecular Biology | volume = 30 | issue = 7 | pages = 948–57 | date = June 2023 | pmid = 37386214 | doi = 10.1038/s41594-023-01021-8| doi-access = free | pmc = 10352137 | hdl = 2440/139184 | hdl-access = free }}</ref> Trim24 prevents p53 from activating its targets, but only in these regions, effectively giving p53 the ability to 'read out' the histone profile at key target genes and act in a gene-specific manner. {{cn|date=November 2024}}