In vitro studies have described

In vitro studies have described the kinetic parameters of the KDM4A catalytic site (cKDM4A) (Figure 1C) (23); the kcat/KM (kcat as the catalytic constant and KM as the Michaelis constant) values represent how fast the enzyme reacts with the substrate once it encounters the substrate, where the values are proportional to the catalytic efficiency. The kcat/KM values of the dimethylated and trimethylated peptide (2.4 × 10−3 (µmol/L)-1 min-1 and 3.0 × 10−2 (µmol/L)-1 min-1, respectively) show that cKDM4A has a stronger preference for the trimethylated substrate than the dimethylated substrate. Furthermore, a comparison of the kcat/KM values for a modified nucleosome and an analogue trimethylated peptide that has an aminoethylcysteine but behaves in a way similar to that of natural lysine residues suggests that the catalytic site of KDM4A predominantly recognizes the residues immediately surrounding the H3K9 and not additional structures on the nucleosome (Figure 1C). These data suggest that the catalytic site of KDM4A acts in a distributive manner and that the recognition of other prostaglandin receptors features or modifications by the double Tudor or PHD domains of the entire demethylase may result in a tighter association, additional interactions, and an increase in demethylase activity (23). Such interactions and protein–protein cross talk may play an important role in the regulation of KDM4A activity and processivity. In vivo, in the presence of chromatin histone marks or protein partners, the entire KDM4A may demethylate in a processive manner, and this regulation of KDM4A has significant implications on the specific output of KDM4 proteins in a context-dependent manner 31, 36, 37, 38, 39. Additionally, the demethylation activity toward H3K9me3 is influenced by other posttranslational modifications on the same peptide. Further studies of these cross-talk interactions at the peptide level are needed to obtain a more accurate understanding of the dynamics of epigenetic marks (40). Due to its catalytic activity, interactions, particular structure, and recognition ability, several functions have been attributed to KDM4A. Below, we describe some functions of KDM4A.
KDM4A functions Through KDM4A activity, H3K9me3 demethylation promotes an open chromatin state, contributing to the transcription activation of promoter regions (Figure 2A) (48). Regarding the functional impact of KDM4A-mediated demethylation of H3K36, the outcome is less clear. Notably, H3K36 and H3K27 methylation are antagonistic histone marks, because nucleosomes that are methylated at H3K27 inhibit the enzymatic methylation of H3K36 and vice versa (49). Whereas H3K27 methylation is a characteristic repressive histone mark that is associated with the Polycomb group, H3K36me3 histone modification has been implicated in other processes that affect euchromatin functions. For example, H3K36me3 is recognized by proteins that antagonize exon definition, affecting alternative splicing 50, 51. The role of H3K36me3 in transcription is controversial. Whereas some investigators have demonstrated that H3K36me3 couples with RNA polymerase II (RNA Pol II) in transcription elongation (52), others have shown that H3K36me3 is recognized by DNMT3A, promoting DNA methylation at nearby DNA regions and suggesting a DNMT3A-mediated gene repression link to H3K36me3 (53). KDM4A is implicated in replication timing and genomic stability (45). KDM4A overexpression in human cells increases chromatin accessibility, coinciding with accelerated replication during S phase (Figure 2B). In contrast, a mutation in the Caenorhabditis elegans orthologue leads to increased replication timing and DNA damage, which induces p53-dependent apoptosis. KDM4A abundance is cell cycle-dependent, and this protein antagonizes the function of heterochromatin protein 1 gamma (HP1γ) (45). Additionally, KDM4A is involved in the DNA damage response through the tandem Tudor domains of KDM4A and KDM4B that bind to the preexisting methylated residues of H4. After DNA damage, KDM4A/B is ubiquitinated by RNF8 and RNF168 and degraded by the proteasome, allowing the binding of 53BP1 to H4K20me2. Furthermore, KDM4A overexpression abrogates 53BP1 recruitment to DNA damage sites, suggesting a possible role of KDM4A in the DNA damage response (Figure 2C) (46).