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Review
. 2019 May;19(5):3963-3971.
doi: 10.3892/mmr.2019.10111. Epub 2019 Apr 1.

Regulation of histone arginine methylation/demethylation by methylase and demethylase (Review)

Jing Zhang  1 , Li Jing  1 , Menghan Li  1 , Lingfeng He  1 , Zhigang Guo  1
Affiliations
Review

Regulation of histone arginine methylation/demethylation by methylase and demethylase (Review)

Jing Zhang et al. Mol Med Rep. 2019 May.

Abstract

Histone arginine methylation is a universal post‑translational modification that has been implicated in multiple cellular and sub‑cellular processes, including pre‑mRNA splicing, DNA damage signaling, mRNA translation, cell signaling and cell death. Despite these important roles, the understanding of its regulation with respect to certain other modifications, such as phosphorylation and acetylation, is very poor. Thus far, few histone arginine demethylases have been identified in mammalian cells, compared with nine protein arginine methyltransferases (PRMTs) that have been reported. Studies have reported that aberrant histone arginine methylation is strongly associated with carcinogenesis and metastasis. This increases the requirement for understanding the regulation of histone arginine demethylation. The present review summarizes the published studies and provides further insights into histone arginine methylases and demethylases.

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Figures

Figure 1.
Figure 1.
Overview of the human PRMT family. The catalytic methyltransferase domains contain a conserved binding domain (grey) with conserved motifs (black) that are important for the enzymatic reaction. Additional motifs: SH3 domain, zinc finger domain, myristoylation motif, FBox motif. PRMT, protein arginine methyltransferase.
Figure 2.
Figure 2.
Mechanism and demethylase activity of PAD4. PAD4 demethylates H3 and H4. The two possible mechanisms of the PAD4 reaction with methylated arginine in a protein substrate are presented. PAD4, peptidyl arginine deaminase 4; Cit, citrulline.
Figure 3.
Figure 3.
Mechanism and demethylase activity of JMJD6. The two demethylation steps catalyzed by JMJD6 are presented. Firstly, JMJD6 hydroxylates the methyl group consuming oxoglutarate (2OG), and a subsequent deformylation reaction produces formaldehyde (CH2O). JMJD6, Jumonji domain-containing protein 6.
Figure 4.
Figure 4.
Demethylation mechanism of lysine and arginine. (A) Mechanism for JmjC-catalyzed lysine demethylation. JmjC lysine demethylases catalyze oxidative decarboxylation of 2OG to form succinate, carbon dioxide and a reactive iron(IV)-oxo intermediate. Fragmentation of the hemiaminal releases formaldehyde and the unmethylated lysine residue. (B) Proposed mechanism for JmjC-catalyzed arginine demethylation, a reaction which is analogous to lysine demethylation. JmjC, JumonjiC; KDM, lysine-specific histone demethylase; RDM, arginine-specific histone demethylase.
Figure 5.
Figure 5.
Demethylation activity exists at a 30–50% (NH4)2SO4 precipitation of HeLa nuclear extract. Dot immunoblot analysis of H4R3 me2s following incubation with nuclear extract. Avidin served as a loading control. Western blot analysis represents the results of one experiment, representative of three independent experiments. Student's t-test was performed. **P<0.01 vs. CTL. CTL, control.
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