| 背景 | Most PKMT substrates are histone proteins and transcription factors, emphasizing the importance of lysine methylation in regulating chromatin structure and gene expression. Lys9 of histone H3 is mono- or di-methylated by G9A/GLP and tri-methylated by SETDB1 to activate transcription. JHDM3A-mediated demethylation of the same residue creates mono-methyl Lys9 and inhibits gene transcription . Tumor suppressor p53 is regulated by methylation of at least four sites. p53-mediated transcription is repressed following mono-methylation of p53 at Lys370 by SMYD2; di-methylation at the same residue further inhibits p53 by preventing association with 53BP1. Concomitant di-methylation at Lys382 inhibits p53 ubiquitination following DNA damage. Mono-methylation at Lys382 by SET8 suppresses p53 transcriptional activity, while SET7/9 mono-methylation at Lys372 inhibits SMYD2 methylation at Lys370 and stabilizes the p53 protein. Di-methylation at Lys373 by G9A/GLP inhibits p53-mediated apoptosis and correlates with tri-methylation of histone H3 Lys9 at the p21 promoter . Overexpression of PKMTs is associated with multiple forms of human cancer, which has generated tremendous interest in targeting protein lysine methyltransferases in drug discovery research. |
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