The Roles of Jumonji-Type Oxygenases in Human Disease

Abstract

The iron- and 2-oxoglutarate-dependent oxygenases constitute a phylogenetically conserved class of enzymes that catalyze hydroxylation reactions in humans by acting on various types of substrates, including metabolic intermediates, amino acid residues in different proteins and various types of nucleic acids. The discovery of jumonji (Jmj), the founding member of a class of Jmj-type chromatin-modifying enzymes and transcriptional regulators, has culminated in the discovery of several branches of histone lysine demethylases, with essential functions in regulating the epigenetic landscape of the chromatin environment. This work has now been considerably expanded into other aspects of epigenetic biology and includes the discovery of enzymatic steps required for methyl-cytosine demethylation, as well as modification of RNA and ribosomal proteins. This overview aims to summarize the current knowledge on the human Jmj-type enzymes and their involvement in human pathological processes, including development, cancer, inflammation and metabolic diseases.

Opposing Chromatin Signals Direct and Regulate the Activity of Lysine Demethylase 4C (KDM4C)

“…Specialized Reader Domains-The KDM4 family of demethylases expanded from predominantly one demethylase to five in the vertebrate lineages (25,27), yet all five of these enzymes act on trimethylated H3K9, a seemingly redundant function (21)(22)(23)(24)(25)(26). Recent in vivo studies demonstrate that KDM4B and KDM4C have overlapping but also distinct targets (1), indicating mechanisms that generate specificity.…”

“…The KDM4 histone demethylases act on H3K9me3/me2 and, in some cases, H3K36me3/me2 (21)(22)(23)(24)(25)(26). In vertebrates, this family is composed of five family mem-bers, KDM4A-E (25,27), but despite their shared histone methylation substrates (21)(22)(23)(24)(25)(26), it appears that at least KDM4B and KDM4C function at distinct genomic loci (1). Whereas KDM4B occupancy is more evenly distributed across different genomic regions, KDM4C localizes predominantly to H3K4me3-containing promoter regions (1,2).…”

Catalytic Mechanisms of Fe(II)- and 2-Oxoglutarate-dependent Oxygenases

“…The Fe(II)/2OG-dependent oxygenases catalyze a variety of oxidative transformations including hydroxylation, halogenation, ring closure, desaturation, epimerization, ring expansion, and epoxidation reactions. Because of their rich oxidative transformation capabilities, these enzymes play important roles in many biological processes (9) including the post-translational modification of collagen (11), fatty acid metabolism (12,13), oxygen sensing (14,15), DNA and RNA repair (16,17), demethylations related to epigenetic regulation (18,19), and the biosynthesis of many antibiotics and other secondary metabolites (20,21).…”

Clipping of arginine-methylated histone tails by JMJD5 and JMJD7

“…Interestingly, proteins of the JmjC domain family have been reported to possess diverse enzymatic activities (6)(7)(8). Generally, these functions are related to the JmjC/cupin-like dioxygenase domain that is the hallmark of this protein family.…”

“…Generally, these functions are related to the JmjC/cupin-like dioxygenase domain that is the hallmark of this protein family. Published activities of various JmjC proteins include demethylation of lysines in histones, demethylation of RNA and DNA, and hydroxylation of various amino acids (6,8,9). While many members of the JmjC protein family have been characterized biochemically, the functions of several members, including JMJD4-JMJD8 and HSPBAP1 remain uncharacterized or controversial.…”