PT  - JOURNAL ARTICLE
AU  - Xueyin Wang
AU  - Yicheng Long
AU  - Richard D. Paucek
AU  - Anne R. Gooding
AU  - Thomas Lee
AU  - Thomas R. Cech
TI  - Regulation of histone methylation by automethylation of PRC2
AID  - 10.1101/343020
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 343020
4099  - http://biorxiv.org/content/early/2018/06/08/343020.short
4100  - http://biorxiv.org/content/early/2018/06/08/343020.full
AB  - Polycomb Repressive Complex 2 (PRC2) is a histone methyltransferase whose function is critical for regulating transcriptional repression in many eukaryotes including humans. Its catalytic moiety EZH2 is responsible for the tri-methylation of H3K27 and also undergoes automethylation. Using mass spectroscopic analysis of recombinant human PRC2, we identified three methylated lysine residues (K510, K514, K515) on a disordered but highly conserved loop of EZH2. These lysines were mostly mono- and di-methylated. Either mutation of these lysines or their methylation increases PRC2 histone methyltransferase activity. In addition, mutation of these three lysines in HEK293T cells using CRISPR genome-editing increases global H3K27 methylation levels. EZH2 automethylation occurs intramolecularly (in cis) by methylation of a pseudosubstrate sequence on the flexible loop. This post-translational modification and cis-regulation of PRC2 are analogous to the activation of many protein kinases by autophosphorylation. We therefore propose that EZH2 automethylation provides a way for PRC2 to modulate its histone methyltransferase activity by sensing histone H3 tails, SAM concentration, and perhaps other effectors.