Reactome | Regulation of TP53 Activity through Methylation

Regulation of TP53 Activity through Methylation

Stable Identifier

R-HSA-6804760

Type

Pathway

Species

Homo sapiens

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Regulation of TP53 Activity through Methylation

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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).

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).

Literature References

PubMed ID	Title	Journal	Year
20870725	The MBT repeats of L3MBTL1 link SET8-mediated p53 methylation at lysine 382 to target gene repression West, LE, Roy, S, Lachmi-Weiner, K, Hayashi, R, Shi, X, Appella, E, Kutateladze, TG, Gozani, O	J. Biol. Chem.	2010
17805299	p53 is regulated by the lysine demethylase LSD1 Huang, J, Sengupta, R, Espejo, AB, Lee, MG, Dorsey, JA, Richter, M, Opravil, S, Shiekhattar, R, Bedford, MT, Jenuwein, T, Berger, SL	Nature	2007
15186775	Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53 An, W, Kim, J, Roeder, RG	Cell	2004
16415881	Structural basis for the methylation site specificity of SET7/9 Couture, JF, Collazo, E, Hauk, G, Trievel, RC	Nat. Struct. Mol. Biol.	2006
15448695	A new effector pathway links ATM kinase with the DNA damage response Demonacos, C, Krstic-Demonacos, M, Smith, L, Xu, D, O'Connor, DP, Jansson, M, La Thangue, NB	Nat. Cell Biol.	2004
18833288	ATM and Chk2 kinase target the p53 cofactor Strap Adams, CJ, Graham, AL, Jansson, M, Coutts, AS, Edelmann, M, Smith, L, Kessler, B, La Thangue, NB	EMBO Rep.	2008
21625555	Modeling a new water channel that allows SET9 to dimethylate p53 Bai, Q, Shen, Y, Yao, X, Wang, F, Du, Y, Wang, Q, Jin, N, Hai, J, Hu, T, Yang, J	PLoS ONE	2011
17108971	Repression of p53 activity by Smyd2-mediated methylation Huang, J, Perez-Burgos, L, Placek, BJ, Sengupta, R, Richter, M, Dorsey, JA, Kubicek, S, Opravil, S, Jenuwein, T, Berger, SL	Nature	2006
10518217	A novel cofactor for p300 that regulates the p53 response Shikama, N, Lee, CW, France, S, Delavaine, L, Lyon, J, Krstic-Demonacos, M, La Thangue, NB	Mol. Cell	1999
20118233	G9a and Glp methylate lysine 373 in the tumor suppressor p53 Huang, J, Dorsey, J, Chuikov, S, Perez-Burgos, L, Zhang, X, Jenuwein, T, Reinberg, D, Berger, SL	J. Biol. Chem.	2010
11511361	A TPR motif cofactor contributes to p300 activity in the p53 response Demonacos, C, Krstic-Demonacos, M, La Thangue, NB	Mol. Cell	2001
15525938	Regulation of p53 activity through lysine methylation Chuikov, S, Kurash, JK, Wilson, JR, Xiao, B, Justin, N, Ivanov, GS, McKinney, K, Tempst, P, Prives, C, Gamblin, SJ, Barlev, NA, Reinberg, D	Nature	2004
22362889	The p53 cofactor Strap exhibits an unexpected TPR motif and oligonucleotide-binding (OB)-fold structure Adams, CJ, Pike, AC, Maniam, S, Sharpe, TD, Coutts, AS, Knapp, S, La Thangue, NB, Bullock, AN	Proc. Natl. Acad. Sci. U.S.A.	2012