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Review
. 2019 Apr;1871(2):406-418.
doi: 10.1016/j.bbcan.2019.04.002. Epub 2019 Apr 26.

The small members of the JMJD protein family: Enzymatic jewels or jinxes?

Sangphil Oh  1 , Sook Shin  1 , Ralf Janknecht  2
Affiliations
Review

The small members of the JMJD protein family: Enzymatic jewels or jinxes?

Sangphil Oh et al. Biochim Biophys Acta Rev Cancer. 2019 Apr.

Abstract

Jumonji C domain-containing (JMJD) proteins are mostly epigenetic regulators that demethylate histones. However, a hitherto neglected subfamily of JMJD proteins, evolutionarily distant and characterized by their relatively small molecular weight, exerts different functions by hydroxylating proteins and RNA. Recently, unsuspected proteolytic and tyrosine kinase activities were also ascribed to some of these small JMJD proteins, further increasing their enzymatic versatility. Here, we discuss the ten human small JMJD proteins (HIF1AN, HSPBAP1, JMJD4, JMJD5, JMJD6, JMJD7, JMJD8, RIOX1, RIOX2, TYW5) and their diverse physiological functions. In particular, we focus on the roles of these small JMJD proteins in cancer and other maladies and how they are modulated in diseased cells by an altered metabolic milieu, including hypoxia, reactive oxygen species and oncometabolites. Because small JMJD proteins are enzymes, they are amenable to inhibition by small molecules and may represent novel targets in the therapy of cancer and other diseases.

Keywords: Cancer; Demethylation; Hydroxylation; Jumonji; Oncometabolite.

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Conflict of interest statement

Competing interests statement

The authors declare that there is no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Phylogenetic relationship amongst the 33 human JMJD proteins. Whole protein sequences (see Table 1) were aligned with the Clustal Omega algorithm and a phylogenetic tree generated with PhyML, using the JTT amino acid substitution model as implemented in SeaView version 4 [197]. The yellow quadrant highlights the evolutionarily separated small JMJD proteins. All other proteins marked in black color have a calculated molecular weight in excess of 100 kDa (except for JMJD2D-F), have been reported to demethylate histone lysine residues (except for JARID2 and JMJD2F), and are not discussed in this review.
Fig. 2.
Fig. 2.
Oxygen- and 2OG-dependent catalytic activities displayed by JMJD proteins. (A) Demethylation of a monomethylated lysine residue. The first step is the hydroxylation of the methyl moiety, leading to a labile carbinolamine that spontaneously releases formaldehyde. Di- and trimethylated lysine residues are also utilized as substrates by several JMJD proteins. (B, C) Hydroxylation of an asparagine or aspartate residue by HIF1AN. (D) Hydroxylated histidine residue as a consequence of HIF1AN or RIOX1\2 catalytic activity. (E-G) Hydroxylation of lysine at the C4, C5 or C3 position by JMJD4, JMJD6 or JMJD7, respectively. (H) JMJD5- mediated hydroxylation at the C3 position of an arginine residue. (I) Hydroxywybutosine. Please note that TYW5 hydroxylates a precursor of wybutosine, after which TYW4 catalyzes the addition of further modifications (marked in blue color). In all panels, red color highlights the oxygen added upon JMJD catalytic activity.
Fig. 3.
Fig. 3.
The human JMJD7-PLA2G4B fusion protein that is composed of JMJD7 amino acids 1–234 and PLA2G4B amino acids 4–781. Protein sequences for JMJD7 (NP_001108104.1), JMJD7-PLA2G4B (NP_005081.1) and PLA2G4B (NP_001108105.1) were derived from NCBI.
Fig. 4.
Fig. 4.
Oncometabolites (fumarate, succinate, 2-hydroxyglutarate) and their negative impact on 2OG-dependent activities of JMJD proteins. Inactivating mutations of the Krebs cycle enzymes SDH, FH and MDH have been found in various tumors; likewise, neomorphic mutants of IDH (IDHmut) have been associated with cancer.
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