Regulation of TP53 Activity through Methylation

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R-HSA-6804760
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Pathway
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Homo sapiens
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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
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
11511361 A TPR motif cofactor contributes to p300 activity in the p53 response

Demonacos, C, Krstic-Demonacos, M, La Thangue, NB

Mol. Cell 2001
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
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
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
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
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
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
16415881 Structural basis for the methylation site specificity of SET7/9

Couture, JF, Collazo, E, Hauk, G, Trievel, RC

Nat. Struct. Mol. Biol. 2006
15186775 Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53

An, W, Kim, J, Roeder, RG

Cell 2004
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
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