JmjC

JmjC, short for Jumonji C, designates a large family of proteins defined by the conserved JmjC catalytic domain. The domain is part of the Jumonji C (JmjC) superfamily of Fe(II)/2-oxoglutarate-dependent dioxygenases and is best known for catalyzing the demethylation of lysine residues on histone tails. In humans, JmjC domain-containing proteins function primarily as histone lysine demethylases (KDMs), but some members act on non-histone substrates or perform regulatory roles in chromatin.

Mechanism: The catalytic reaction requires Fe(II) and 2-oxoglutarate as cofactors and uses molecular oxygen to hydroxylate the methyl group on the lysine. This hydroxylated intermediate decomposes to formaldehyde, yielding demethylated lysine and, as byproducts, succinate and CO2. The reaction is coupled to the oxidation of 2-oxoglutarate to succinate.

Scope: JmjC-domain proteins show substrate specificity for various histone lysine marks, including H3K4, H3K9, H3K27, and H3K36 methylation states, among others. The demethylase activities are often combined with other chromatin-targeting or recruitment domains that guide locus specificity, such as PHD fingers, ARID, or zinc-finger motifs.

Biological significance: JmjC demethylases participate in development, cell differentiation, and genome regulation. Dysregulation of JmjC enzymes has been linked to cancer, neurological disorders, and aging. Because their activity is enzymatic and substrate-specific, they are active targets in epigenetic therapy; several inhibitors are used in research, and some are being explored clinically.

History and naming: The name derives from the Drosophila Jumonji gene, whose mutation affects development; the catalytic JmjC domain was later found to confer demethylase activity in multiple proteins.