Abstract
The Jumonji C (JmjC) family of 2-oxoglutarate (2OG)-dependent oxygenases have established roles in the regulation of transcription via the catalysis of demethylation of Nε-methylated lysine residues in histone tails, especially the N-terminal tail of histone H3. Most human JmjC Nɛ-methyl lysine demethylases (KDMs) are complex enzymes, with ‘reader domains’ in addition to their catalytic domains. Recent biochemical evidence has shown that some, but not all, JmjC KDMs also have Nω-methyl arginyl demethylase (RDM) activity. JmjC KDM activity has been linked to multiple cancers and some JmjC proteins are therapeutic targets. It is, therefore, important to test not only whether compounds in development inhibit the KDM activity of targeted JmjC demethylases, but also whether they inhibit other activities of these proteins. Here we report biochemical studies on the potential dual inhibition of JmjC KDM and RDM activities using a model JmjC demethylase, KDM4E (JMJD2E). The results reveal that all of the tested compounds inhibit both the KDM and RDM activities, raising questions about the in vivo effects of the inhibitors.This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.
Highlights
In organisms varying from bacteria to humans, 2-oxoglutarate (2OG) and Fe(II)dependent oxygenases play important roles in the regulation of gene expression and protein biosynthesis [1,2,3]
The results reveal that the JmjC KDM inhibitors inhibit residue demethylation (RDM) activity of KDM4E, raising questions regarding the mode(s) of action of the inhibitors in the cellular context
To investigate whether JmjC KDM inhibitors inhibit RDM activity, we elected to work with KDM4E, a likely pseudo gene in humans
Summary
In organisms varying from bacteria to humans, 2-oxoglutarate (2OG) and Fe(II)dependent oxygenases play important roles in the regulation of gene expression and protein biosynthesis (figure 1) [1,2,3]. The 2OG-dependent hypoxia inducible factor (HIF) hydroxylases were the first such enzymes shown to have a role in transcriptional regulation. A second type of 2OG oxygenase-dependent HIF-a modification is catalysed by factor inhibiting HIF (FIH), which regulates HIF activity. FIH is one of the JmjC ‘hydroxylases’ that catalyse the formation of stable alcohol products [6,15] Such enzymes include the ribosomal/protein oxygenases and related 2OG oxygenases catalysing modification of the translational machinery [15 –17] (figure 1). There is good evidence that FIH accepts multiple non-HIF substrates—many from the ankyrin repeat domains (ARD) structural family— but it can catalyse the hydroxylation of residues other than asparagine, including aspartyl- and histidyl-residues [21,31]. The results reveal that the JmjC KDM inhibitors inhibit RDM activity of KDM4E, raising questions regarding the mode(s) of action of the inhibitors in the cellular context
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
