Protein arginine methylation/demethylation and cancer

Abstract

Protein arginine methylation is a common post-translational modification involved in numerous cellular processes including transcription, DNA repair, mRNA splicing and signal transduction. Currently, there are nine known members of the protein arginine methyltransferase (PRMT) family, but only one arginine demethylase has been identified, namely the Jumonji domain-containing 6 (JMJD6). Although its demethylase activity was initially challenged, its dual activity as an arginine demethylase and a lysine hydroxylase is now recognized. Interestingly, a growing number of substrates for arginine methylation and demethylation play key roles in tumorigenesis. Though alterations in the sequence of these enzymes have not been identified in cancer, their overexpression is associated with various cancers, suggesting that they could constitute targets for therapeutic strategies. In this review, we present the recent knowledge of the involvement of PRMTs and JMJD6 in tumorigenesis.

Keywords: JMJD6; PRMT; cancer; demethylation; methylation.

Figure 1. Mechanism of protein methylation on arginine residues

Monomethylation (MMA) is catalyzed on one of the terminal guanidino-nitrogen atom of an arginine by Type I, II and III protein arginine methyltransferase (PRMTs). The enzymatic reaction consumes a methyl donor, S-adenosylmethyionine (AdoMet) and generates S-adenosylhomocysteine (AdoHcy). Type I PRMTs generate asymmetric dimethylation (ADMA) and Types II PRMTs are responsible for symmetric dimethylation (SDMA)

Figure 2. Functional domains and demethylase activity of JMJD6

A. The different functional domains of the JMJD6 protein are presented. NLS: Nuclear localization signal. B. Demethylation reaction of a monomethylated arginine is catalyzed by JMJD6 within 2 steps. First JMJD6 hydroxylates the methyl group consuming oxoglutarate (2OG), then a deformylation reaction produces formaldehyde (CH₂O) leading to an unmodified arginine

Figure 3. The functions of JMJD6 in cells

Red dots represent methylation events, and OH hydroxylation reactions. A. Epigenetic regulation. JMJD6 catalyzes the demethylation (red arrow) of histone H3 (H3R2me2) and histone H4 (H4R3me2), and lysine hydroxylation (purple arrow) of histones H3, H4, H2A and H2B. B. Regulation of transcriptional pause release on distal anti-pause enhancers (APE) of a subset of transcriptional units. JMJD6 catalyzes H4R3me2 demethylation and RNA demethylation in the cap structure of 7SK snRNA (orange dot), and is responsible for pause release and transcription elongation. C. Retinoic acid-mediated RARβ2 gene regulation. Upon RA stimulation (purple dots), RARα, RXRα, HSP70, Carm1 and coactivator complexes (Coact cplx) bind on RARβ2 gene promoter (RARE). Carm1-methylation of HSP70 allows the recruitment of the preinitiation complex (TFIIH) and expression of RARβ2 genes. JMJD6 demethylation reverses this process. D. Pre-mRNA splicing regulation. Lysine hydroxylation by JMJD6 of U2AF65 (K15, K276) and SR-like proteins (SR-P) regulates alternative splicing. For example, VEGR receptor gene splicing is regulated by U2AF65 hydroxylation. E. Repression of p53 transcriptional activity. JMJD6 catalyzes p53 hydroxylation. This event antagonizes p53 acetylation and promotes the interaction of p53 with the transcriptional repressor Mdmx resulting in inhibition of apoptosis and cell cycle arrest. F. Phagocytosis regulation. JMJD6 is localized at the cell surface of immature macrophages in order to regulate phagocytosis. G. Regulation of estrogen non-genomic action. Upon E2 stimulation (green dots), ERα is methylated by PRMT1. This event is a prerequisite to the recruitment of PI3K and Src, and the activation of Akt. JMJD6 demethylates ERα, promoting the dissociation of the complex. H. Control of innate immune responses. Toll like receptor (TLR) ligands induce PRMT1 degradation. JMJD6 demethylates TRAF6 leading to full NF-κB activation. I. Regulation of foot-and-mouth disease virus (FMDV) infection. FMDV infection relocalizes JMJD6 in the nucleus where it will demethylate RNA helicase A (RHA). RHA methylated exits from the nucleus and interacts in the cytoplasm with the replication machinery