Regulation of TP53 Activity through Methylation (Homo sapiens)

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3, 4, 6, 9-11, 13...2015, 18123212411, 13, 16199, 14, 17159, 14nucleoplasmcytosolSMYD2Me-K382,p-S15,S20-TP53 TetramerTTC5JMYEHMT2 UBC(457-532) UBB(153-228) p-S203,S221-TTC5:EP300:JMYAdoHcySETD8UBA52(1-76) Me1-K372,p-S15,S20-TP53 Tetramerp-S15,S20,Me-R333,Me2-R335,R337-TP53 UBC(153-228) Me1-K370,p-S15,S20-TP53 TetramerEP300 UBC(305-380) EHMT1 PRMT5 p-S15,S20-TP53 UBC(609-684) AdoHcyp-S203,S221-TTC5 JMY p-S203,S221-TTC5 AdoMetPRMT5MDM4 SETD9EP300 L3MBTL1PolyUb-JMYAdoMetPRMT5 L3MBTL1:Me-K382,p-S-15,S20-TP53UBC(381-456) UBC(77-152) p-S166,S188-MDM2 AdoHcyp-S203,S221-TTC5 UBC(229-304) UBB(1-76) p-S15,S20-TP53Tetramer:p-S203,S221-TTC5:EP300:JMYJMY p-S166,S188-MDM2dimer,p-S166,S188-MDM2:MDM4TP53 TetramerATPADPp-S15,S20-TP53 JMY p-S15,S20-TP53Tetramer:p-S203,S221-TTC5:EP300:JMY:PRMT5p-S1981,Ac-K3016-ATMADPEHMT1:EHMT2Me-K382,p-S15,S20-TP53 UBB(77-152) JMY UBC(533-608) Me1-K372,p-S15,S20-TP53 p-S203-TTC5p-S203,S221-TTC5 ATPL3MBTL1 p-S,3T-CHEK2UbMe-K382,p-S15,S20-TP53 p-S15,S20,Me-R333,Me2-R335,R337-TP53 Tetramer:p-S203,S221-TTC5:EP300:JMY:PRMT5MeK-370,p-S15,S20-TP53 EP300 EP300 Me2-K373-TP53 EP300p-S203,S221-TTC5UBC(1-76) p-S15,S20-TP53 p-S15,S20-TP53TetramerMe2-K373-TP53TetramerTP53 RPS27A(1-76) AdoMet81, 5, 79, 1411, 13, 16129, 14412


TP53 (p53) undergoes methylation on several lysine and arginine residues, which modulates its transcriptional activity.

PRMT5, recruited to TP53 as part of the ATM-activated complex that includes TTC5, JMY and EP300 (p300), methylates TP53 arginine residues R333, R335 and R337. PRMT5-mediated methylation promotes TP53-stimulated expression of cell cycle arrest genes (Shikama et al. 1999, Demonacos et al. 2001, Demonacos et al. 2004, Adams et al. 2008, Adams et al. 2012). SETD9 (SET9) methylates TP53 at lysine residue K372, resulting in increased stability and activity of TP53 (Chuikov et al. 2004, Couture et al. 2006, Bai et al. 2011).<p>TP53 transcriptional activity is repressed by SMYD2-mediated methylation of TP53 at lysine residue K370 (Huang et al. 2006). Dimethylation of TP53 at lysine residue K373 by the complex of methyltransferases EHMT1 and EHMT2 also represses TP53-mediated transcription (Huang et al. 2010). The chromatin compaction factor L3MBTL1 binds TP53 monomethylated at lysine K382 by SETD8 (SET8) and, probably through changing local chromatin architecture, represses transcription of TP53 targets (West et al. 2010). The histone lysine-specific demethylase LSD1 interacts with TP53 and represses p53-mediated transcriptional activation (Huang et al. 2007). PRMT1 and CARM1 can also modulate p53 functions in a cooperative manner (An et al. 2004). View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 6804760
Reactome version: 64
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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  1. Demonacos C, Krstic-Demonacos M, Smith L, Xu D, O'Connor DP, Jansson M, La Thangue NB.; ''A new effector pathway links ATM kinase with the DNA damage response.''; PubMed Europe PMC Scholia
  2. Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, Opravil S, Shiekhattar R, Bedford MT, Jenuwein T, Berger SL.; ''p53 is regulated by the lysine demethylase LSD1.''; PubMed Europe PMC Scholia
  3. Cheng Q, Cross B, Li B, Chen L, Li Z, Chen J.; ''Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage.''; PubMed Europe PMC Scholia
  4. Jansson M, Durant ST, Cho EC, Sheahan S, Edelmann M, Kessler B, La Thangue NB.; ''Arginine methylation regulates the p53 response.''; PubMed Europe PMC Scholia
  5. Adams CJ, Graham AL, Jansson M, Coutts AS, Edelmann M, Smith L, Kessler B, La Thangue NB.; ''ATM and Chk2 kinase target the p53 cofactor Strap.''; PubMed Europe PMC Scholia
  6. Huang J, Perez-Burgos L, Placek BJ, Sengupta R, Richter M, Dorsey JA, Kubicek S, Opravil S, Jenuwein T, Berger SL.; ''Repression of p53 activity by Smyd2-mediated methylation.''; PubMed Europe PMC Scholia
  7. Chuikov S, Kurash JK, Wilson JR, Xiao B, Justin N, Ivanov GS, McKinney K, Tempst P, Prives C, Gamblin SJ, Barlev NA, Reinberg D.; ''Regulation of p53 activity through lysine methylation.''; PubMed Europe PMC Scholia
  8. Demonacos C, Krstic-Demonacos M, La Thangue NB.; ''A TPR motif cofactor contributes to p300 activity in the p53 response.''; PubMed Europe PMC Scholia
  9. Pant V, Xiong S, Iwakuma T, Quintás-Cardama A, Lozano G.; ''Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability.''; PubMed Europe PMC Scholia
  10. Huang L, Yan Z, Liao X, Li Y, Yang J, Wang ZG, Zuo Y, Kawai H, Shadfan M, Ganapathy S, Yuan ZM.; ''The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo.''; PubMed Europe PMC Scholia
  11. Tachibana M, Ueda J, Fukuda M, Takeda N, Ohta T, Iwanari H, Sakihama T, Kodama T, Hamakubo T, Shinkai Y.; ''Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9.''; PubMed Europe PMC Scholia
  12. Bai Q, Shen Y, Yao X, Wang F, Du Y, Wang Q, Jin N, Hai J, Hu T, Yang J.; ''Modeling a new water channel that allows SET9 to dimethylate p53.''; PubMed Europe PMC Scholia
  13. Huang J, Dorsey J, Chuikov S, Pérez-Burgos L, Zhang X, Jenuwein T, Reinberg D, Berger SL.; ''G9a and Glp methylate lysine 373 in the tumor suppressor p53.''; PubMed Europe PMC Scholia
  14. An W, Kim J, Roeder RG.; ''Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53.''; PubMed Europe PMC Scholia
  15. Coutts AS, Boulahbel H, Graham A, La Thangue NB.; ''Mdm2 targets the p53 transcription cofactor JMY for degradation.''; PubMed Europe PMC Scholia
  16. Adams CJ, Pike AC, Maniam S, Sharpe TD, Coutts AS, Knapp S, La Thangue NB, Bullock AN.; ''The p53 cofactor Strap exhibits an unexpected TPR motif and oligonucleotide-binding (OB)-fold structure.''; PubMed Europe PMC Scholia
  17. Shi X, Kachirskaia I, Yamaguchi H, West LE, Wen H, Wang EW, Dutta S, Appella E, Gozani O.; ''Modulation of p53 function by SET8-mediated methylation at lysine 382.''; PubMed Europe PMC Scholia
  18. Couture JF, Collazo E, Hauk G, Trievel RC.; ''Structural basis for the methylation site specificity of SET7/9.''; PubMed Europe PMC Scholia
  19. West LE, Roy S, Lachmi-Weiner K, Hayashi R, Shi X, Appella E, Kutateladze TG, Gozani O.; ''The MBT repeats of L3MBTL1 link SET8-mediated p53 methylation at lysine 382 to target gene repression.''; PubMed Europe PMC Scholia
  20. Shikama N, Lee CW, France S, Delavaine L, Lyon J, Krstic-Demonacos M, La Thangue NB.; ''A novel cofactor for p300 that regulates the p53 response.''; PubMed Europe PMC Scholia


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112508view15:46, 9 October 2020ReactomeTeamReactome version 73
101420view11:30, 1 November 2018ReactomeTeamreactome version 66
100958view21:07, 31 October 2018ReactomeTeamreactome version 65
100495view19:41, 31 October 2018ReactomeTeamreactome version 64
100040view16:24, 31 October 2018ReactomeTeamreactome version 63
99593view14:58, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99212view12:43, 31 October 2018ReactomeTeamreactome version 62
93945view13:46, 16 August 2017ReactomeTeamreactome version 61
93535view11:26, 9 August 2017ReactomeTeamreactome version 61
88147view13:02, 26 July 2016RyanmillerOntology Term : 'transcription pathway' added !
88146view13:01, 26 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86634view09:22, 11 July 2016ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
EHMT1 ProteinQ9H9B1 (Uniprot-TrEMBL)
EHMT1:EHMT2ComplexR-HSA-3788728 (Reactome)
EHMT2 ProteinQ96KQ7 (Uniprot-TrEMBL)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
EP300ProteinQ09472 (Uniprot-TrEMBL)
JMY ProteinQ8N9B5 (Uniprot-TrEMBL)
JMYProteinQ8N9B5 (Uniprot-TrEMBL)
L3MBTL1 ProteinQ9Y468 (Uniprot-TrEMBL)
L3MBTL1:Me-K382,p-S-15,S20-TP53ComplexR-HSA-3222113 (Reactome)
L3MBTL1ProteinQ9Y468 (Uniprot-TrEMBL)
MDM4 ProteinO15151 (Uniprot-TrEMBL)
Me-K382,p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
Me-K382,p-S15,S20-TP53 TetramerComplexR-HSA-3222119 (Reactome)
Me1-K370,p-S15,S20-TP53 TetramerComplexR-HSA-3222230 (Reactome)
Me1-K372,p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
Me1-K372,p-S15,S20-TP53 TetramerComplexR-HSA-6805731 (Reactome)
Me2-K373-TP53 TetramerComplexR-HSA-6805762 (Reactome)
Me2-K373-TP53 ProteinP04637 (Uniprot-TrEMBL)
MeK-370,p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
PRMT5 ProteinO14744 (Uniprot-TrEMBL)
PRMT5ProteinO14744 (Uniprot-TrEMBL)
PolyUb-JMYProteinQ8N9B5 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SETD8ProteinQ9NQR1 (Uniprot-TrEMBL)
SETD9ProteinQ8NE22 (Uniprot-TrEMBL)
SMYD2ProteinQ9NRG4 (Uniprot-TrEMBL)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
TTC5ProteinQ8N0Z6 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UbComplexR-HSA-68524 (Reactome)
p-S,3T-CHEK2ProteinO96017 (Uniprot-TrEMBL)
p-S15,S20,Me-R333,Me2-R335,R337-TP53 ProteinP04637 (Uniprot-TrEMBL)
p-S15,S20,Me-R333,Me2-R335,R337-TP53 Tetramer:p-S203,S221-TTC5:EP300:JMY:PRMT5ComplexR-HSA-6804385 (Reactome)
p-S15,S20-TP53 Tetramer:p-S203,S221-TTC5:EP300:JMY:PRMT5ComplexR-HSA-6804371 (Reactome)
p-S15,S20-TP53 Tetramer:p-S203,S221-TTC5:EP300:JMYComplexR-HSA-6804245 (Reactome)
p-S15,S20-TP53 TetramerComplexR-HSA-3222171 (Reactome)
p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)


ComplexR-HSA-6804745 (Reactome)
p-S166,S188-MDM2 ProteinQ00987 (Uniprot-TrEMBL)
p-S1981,Ac-K3016-ATMProteinQ13315 (Uniprot-TrEMBL)
p-S203,S221-TTC5 ProteinQ8N0Z6 (Uniprot-TrEMBL)
p-S203,S221-TTC5:EP300:JMYComplexR-HSA-6804233 (Reactome)
p-S203,S221-TTC5ProteinQ8N0Z6 (Uniprot-TrEMBL)
p-S203-TTC5ProteinQ8N0Z6 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-6804266 (Reactome)
ADPArrowR-HSA-6804276 (Reactome)
ATPR-HSA-6804266 (Reactome)
ATPR-HSA-6804276 (Reactome)
AdoHcyArrowR-HSA-3222237 (Reactome)
AdoHcyArrowR-HSA-6804383 (Reactome)
AdoHcyArrowR-HSA-6805730 (Reactome)
AdoHcyArrowR-HSA-6805740 (Reactome)
AdoHcyArrowR-HSA-6805755 (Reactome)
AdoMetR-HSA-3222237 (Reactome)
AdoMetR-HSA-6804383 (Reactome)
AdoMetR-HSA-6805730 (Reactome)
AdoMetR-HSA-6805740 (Reactome)
AdoMetR-HSA-6805755 (Reactome)
EHMT1:EHMT2mim-catalysisR-HSA-6805755 (Reactome)
EP300R-HSA-6804229 (Reactome)
JMYR-HSA-6804229 (Reactome)
JMYR-HSA-6804253 (Reactome)
L3MBTL1:Me-K382,p-S-15,S20-TP53ArrowR-HSA-3222116 (Reactome)
L3MBTL1R-HSA-3222116 (Reactome)
Me-K382,p-S15,S20-TP53 TetramerArrowR-HSA-6805740 (Reactome)
Me-K382,p-S15,S20-TP53 TetramerR-HSA-3222116 (Reactome)
Me1-K370,p-S15,S20-TP53 TetramerArrowR-HSA-3222237 (Reactome)
Me1-K372,p-S15,S20-TP53 TetramerArrowR-HSA-6805730 (Reactome)
Me2-K373-TP53 TetramerArrowR-HSA-6805755 (Reactome)
PRMT5R-HSA-6804379 (Reactome)
PolyUb-JMYArrowR-HSA-6804253 (Reactome)
R-HSA-3222116 (Reactome) The chromatin compaction factor L3MBTL1 binds TP53 (p53) monomethylated at lysine K382 by lysine methyltransferase SETD8 (SET8). L3MBTL1 binding to TP53 leads to chromatin reorganization at TP53-bound promoters, resulting in repression of gene transcription (West et al. 2010).
R-HSA-3222237 (Reactome) The lysine methyltransferase SMYD2 methylates TP53 (p53) on lysine residue K370, thus repressing TP53 transcriptional activity. The methylation at K370 is inhibited if TP53 is pre-methylated at K372 (Huang et al. 2006).
R-HSA-6804229 (Reactome) JMY forms a complex with EP300 (p300) (Shikama et al. 1999). TTC5 (Strap) interacts with both JMY and EP300 and facilitates the recruitment of JMY to EP300 (Demonacos et al. 2001).
R-HSA-6804242 (Reactome) The complex of JMY, EP300 (p300) and TTC5 (Strap) associates with stabilized TP53 (p53) and enhances transcription of pro-apoptotic TP53 targets, such as BAX (Shikama et al. 1999, Demonacos et al. 2001).
R-HSA-6804253 (Reactome) MDM2 can bind and ubiquitinate JMY, a transcriptional co-factor of TP53 (p53), thus targeting it for proteasome-mediated degradation (Coutts et al. 2007).
R-HSA-6804266 (Reactome) CHEK2 phosphorylates TTC5 (Strap), a cofactor of TP53 (p53), on serine residue S221, resulting in TTC5 stabilization through an unknown mechanism (Adams et al. 2008).
R-HSA-6804276 (Reactome) ATM phosphorylates TTC5 (Strap), a cofactor of TP53 (p53), on serine residue S203. Phosphorylation of S203 induces nuclear accumulation of TTC5, probably by interfering with the nuclear export signal at the N-terminus of TTC5 (Demonacos et al. 2004, Adams et al. 2008).
R-HSA-6804379 (Reactome) TTC5 (Strap) recruits protein arginine methyltransferase PRMT5 to TP53 (p53) (Jansson et al. 2008).
R-HSA-6804383 (Reactome) Protein arginine methyltransferase PRMT5, recruited to TP53 (p53) by TTC5 (Strap), monomethylates TP53 on arginine residue R333 and dimethylates TP53 arginine residues R335 and R337. PRMT5-mediated methylation of TP53 modulates the affinity of TP53 for target promoters, promoting expression of cell cycle arrest genes rather than cell death genes (Jansson et al. 2008).
R-HSA-6805730 (Reactome) The lysine methyltransferase SETD9 methylates TP53 (p53) on lysine residue K372. Methylation at K372 increases stability of TP53 and promotes transcription of TP53 target genes CDKN1A (p21), BAX and MDM2 (Chuikov et al. 2004, Couture et al. 2006). SETD9 may both mono- and dimethylate TP53 (Bai et al. 2011).
R-HSA-6805740 (Reactome) The protein lysine methyltransferase SETD8 (SET8) monomethylates TP53 (p53) on lysine residue K382, resulting in repression of TP53 transcriptional activity (Shi et al. 2007).
R-HSA-6805755 (Reactome) The complex of lysine methyltransferases EHMT1 and EHMT2 dimethylates inactive TP53 at lysine residue K373, resulting in additional inhibition of TP53 activity (Huang et al. 2010).
SETD8mim-catalysisR-HSA-6805740 (Reactome)
SETD9mim-catalysisR-HSA-6805730 (Reactome)
SMYD2mim-catalysisR-HSA-3222237 (Reactome)
TP53 TetramerR-HSA-6805755 (Reactome)
TTC5R-HSA-6804276 (Reactome)
UbR-HSA-6804253 (Reactome)
p-S,3T-CHEK2mim-catalysisR-HSA-6804266 (Reactome)
p-S15,S20,Me-R333,Me2-R335,R337-TP53 Tetramer:p-S203,S221-TTC5:EP300:JMY:PRMT5ArrowR-HSA-6804383 (Reactome)
p-S15,S20-TP53 Tetramer:p-S203,S221-TTC5:EP300:JMY:PRMT5ArrowR-HSA-6804379 (Reactome)
p-S15,S20-TP53 Tetramer:p-S203,S221-TTC5:EP300:JMY:PRMT5R-HSA-6804383 (Reactome)
p-S15,S20-TP53 Tetramer:p-S203,S221-TTC5:EP300:JMY:PRMT5mim-catalysisR-HSA-6804383 (Reactome)
p-S15,S20-TP53 Tetramer:p-S203,S221-TTC5:EP300:JMYArrowR-HSA-6804242 (Reactome)
p-S15,S20-TP53 Tetramer:p-S203,S221-TTC5:EP300:JMYR-HSA-6804379 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-3222237 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6804242 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6805730 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6805740 (Reactome)


mim-catalysisR-HSA-6804253 (Reactome)
p-S1981,Ac-K3016-ATMmim-catalysisR-HSA-6804276 (Reactome)
p-S203,S221-TTC5:EP300:JMYArrowR-HSA-6804229 (Reactome)
p-S203,S221-TTC5:EP300:JMYR-HSA-6804242 (Reactome)
p-S203,S221-TTC5ArrowR-HSA-6804266 (Reactome)
p-S203,S221-TTC5R-HSA-6804229 (Reactome)
p-S203-TTC5ArrowR-HSA-6804276 (Reactome)
p-S203-TTC5R-HSA-6804266 (Reactome)

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