Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases

Abstract

While the oxygen-dependent reversal of lysine Nɛ-methylation is well established, the existence of bona fide Nω-methylarginine demethylases (RDMs) is controversial. Lysine demethylation, as catalysed by two families of lysine demethylases (the flavin-dependent KDM1 enzymes and the 2-oxoglutarate- and oxygen-dependent JmjC KDMs, respectively), proceeds via oxidation of the N-methyl group, resulting in the release of formaldehyde. Here we report detailed biochemical studies clearly demonstrating that, in purified form, a subset of JmjC KDMs can also act as RDMs, both on histone and non-histone fragments, resulting in formaldehyde release. RDM catalysis is studied using peptides of wild-type sequences known to be arginine-methylated and sequences in which the KDM's methylated target lysine is substituted for a methylated arginine. Notably, the preferred sequence requirements for KDM and RDM activity vary even with the same JmjC enzymes. The demonstration of RDM activity by isolated JmjC enzymes will stimulate efforts to detect biologically relevant RDM activity.

Highly selective inhibition of histone demethylases by de novo macrocyclic peptides

“…The importance of the anchoring residue Arg6 within the CP2 sequence for potent KDM4A inhibition, suggests that arginine residues can compete with methylated lysines binding to KDM4A. This is significant, given the recent findings that some, but not all, JmjC-KDMs, including some KDM4 subfamily members, can also act as N ɛ - methyl arginine demethylases26. KDM4A can both catalyse the demethylation of CP2(R6Kme3) and CP2(R6Rme2a), revealing its potential for modulating both lysine and arginine methylation status in non-histone sequences.…”

Fluorescent probes for imaging formaldehyde in biological systems

“…FA is the product of demethylation events of N -methylated amino acid residues (e.g. lysine, arginine, histidine) mediated by demethylase enzymes [9], such as lysine specific demethylase 1 (KDM1) [10,11] and Jumonji domain-containing proteins (Figure 1) [12–14]. FA is also produced through N -demethylation of DNA and RNA bases, such as m 6 A, by AlkB homologues (ALKBH) [15].…”

Clipping of arginine-methylated histone tails by JMJD5 and JMJD7

“…arginine residues within histone tails, although a report showed that some lysine demethylases also have activities against methylated arginines (18). In the hunt for histone arginine demethylase candidates, we hypothesized that one or more orphan JmjC domain-containing proteins, including JMJD4, JMJD5, JMJD7, and JMJD8, may be such a candidate.…”