Regulation of TP53 Activity through Methylation

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. SETD9 (SET9) methylates TP53 at lysine residue K372, resulting in increased stability and activity of TP53.

TP53 transcriptional activity is repressed by SMYD2-mediated methylation of TP53 at lysine residue K370. Dimethylation of TP53 at lysine residue K373 by the complex of methyltransferases EHMT1 and EHMT2 also represses TP53-mediated transcription. 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. The histone lysine-specific demethylase LSD1 interacts with TP53 and represses p53-mediated transcriptional activation. PRMT1 and CARM1 can also modulate p53 functions in a cooperative manner.