Allosteric regulation of histone lysine methyltransferases: from context-specific regulation to selective drugs

Abstract

Histone lysine methyltransferases (HKMTs) are key regulators of many cellular processes. By definition, HKMTs catalyse the methylation of lysine residues in histone proteins. The enzymatic activities of HKMTs are under precise control, with their allosteric regulation emerging as a prevalent paradigm. We review the molecular mechanisms of allosteric regulation of HKMTs using well-studied histone H3 (K4, K9, K27 and K36) methyltransferases as examples. We discuss the current advances and future potential in targeting allosteric sites of HKMTs for drug development.

Elevated expression of nuclear receptor-binding SET domain 3 promotes pancreatic cancer cell growth

“…The nuclear receptor-binding SET domain (NSD) family has three primary members, including NSD1, NSD2, and NSD3 [ 9 – 12 ]. NSD3, also known as WHSC1L1, is a key SET domain-containing histone lysine methyltransferase [ 9 – 12 ].…”

“…The nuclear receptor-binding SET domain (NSD) family has three primary members, including NSD1, NSD2, and NSD3 [ 9 – 12 ]. NSD3, also known as WHSC1L1, is a key SET domain-containing histone lysine methyltransferase [ 9 – 12 ]. NSD3 prefers to recognize and bind to the N-terminal peptides of histone H3 and can dimethylate or trimethylate histone H3 at lysine 36 (H3K36) [ 9 – 12 ].…”

“…NSD3, also known as WHSC1L1, is a key SET domain-containing histone lysine methyltransferase [ 9 – 12 ]. NSD3 prefers to recognize and bind to the N-terminal peptides of histone H3 and can dimethylate or trimethylate histone H3 at lysine 36 (H3K36) [ 9 – 12 ]. In addition, NSD3 has two PWWP (the conserved sequence motif of Pro-Trp-Trp-Pro) domains and five PHD (plant homeodomain) fingers.…”

“…In addition, NSD3 has two PWWP (the conserved sequence motif of Pro-Trp-Trp-Pro) domains and five PHD (plant homeodomain) fingers. These domains are important for chromatin-associated biological processes through interacting with the histones and DNA reader or modifier proteins [ 9 – 12 ]. Studies have shown that NSD3 is essential for regulating a number of key biological processes, including chromatin modification, transcriptional regulation, and DNA repair [ 9 – 12 ].…”

Not just a writer: PRC2 as a chromatin reader

“…This mechanism triggers a positive feedback loop that promotes the amplification and maintenance of the H3K27me3 mark at target sites [ 8–10 ]. The structural basis for this allosteric activation has been established [ 8 , 9 , 11 ]: The H3K27me3-modified lysine binds to an aromatic cage in the PRC2 subunit EED, which in turn leads to the stabilization of the catalytic center in its active conformation (reviewed in [ 5 , 12 ]). Notably, PRC2 can methylate specific lysines on JARID2 [ 13 ] and PALI1 [ 14 ], which can then bind to the same aromatic cage to trigger an allosteric activation [ 13 , 14 ].…”