InterPro domain: IPR039994

The JmjN and JmjC domains are two non-adjacent domains which have been identified in the jumonji family of transcription factors. Although it was originally suggested that the JmjN and JmjC domains always co-occur and might form a single functional unit within the folded protein, the JmjC domain was later found without the JmjN domain in organisms from bacteria to human [ 1 , 2 ].

Proteins containing JmjC domain are predicted to be metalloenzymes that adopt the cupin fold and are candidates for enzymes that regulate chromatin remodelling [ 3 ]. The cupin fold is a flattened beta-barrel structure containing two sheets of five antiparallel beta strands that form the walls of a zinc-binding cleft. Based on the crystal structure of JmjC domain containing protein FIH and JHDM3A/JMJD2A, the JmjC domain forms an enzymatically active pocket that coordinates Fe(III) and alphaKG. Three amino-acid residues within the JmjC domain bind to the Fe(II) cofactor and two additional residues bind to alphaKG [ 3 ].

JmjC domains were identified in numerous eukaryotic proteins containing domains typical of transcription factors, such as PHD, C2H2, ARID/BRIGHT and zinc fingers [ 4 , 4 ]. The JmjC has been shown to function in a histone demethylation mechanism that is conserved from yeast to human [ 5 ]. JmjC domain proteins may be protein hydroxylases that catalyse a novel histone modification [ 6 ]. The human JmjC protein named Tyw5p unexpectedly acts in the biosynthesis of a hypermodified nucleoside, hydroxy-wybutosine, in tRNA-Phe by catalysing hydroxylation [ 7 ].

This entry includes proteins with a JmjC domain. Proteins are biofunctional, acting as histone lysine demethylases and ribosomal histidine hydroxylases. Proteins include:

• Bifunctional lysine-specific demethylase and histidyl-hydroxylase NO66 (also known as Jumanjic domain protein 1) [ 8 ].
• Ribosomal oxygenase 1 (also known as ribosomal oxygenase NO66), which specifically demethylates 'Lys-4' (H3K4me) and 'Lys-36' (H3K36me) of histone H3 [ 9 ].
• Ribosomal oxygenase 2, which demethylates trimethylated 'Lys-9' on histone H3 (H3K9me3), leading to an increase in ribosomal RNA expression [ 10 ]. It also hydroxylates 60S ribosomal protein L27a on 'His-39' [ 11 ].
• 50S ribosomal protein L16 3-hydroxylase from Escherichia coli, which catalyzes the hydroxylation of 50S ribosomal protein L16 on 'Arg-81' [ 11 ].

1. Evidence of domain swapping within the jumonji family of transcription factors. Trends Biochem. Sci. 25, 274-6
2. JmjC: cupin metalloenzyme-like domains in jumonji, hairless and phospholipase A2beta. Trends Biochem. Sci. 26, 7-9
3. JmjC-domain-containing proteins and histone demethylation. Nat. Rev. Genet. 7, 715-27
4. Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1 alpha. J. Biol. Chem. 278, 1802-6
5. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811-6
6. Methylation: lost in hydroxylation? EMBO Rep. 6, 315-20
7. Expanding role of the jumonji C domain as an RNA hydroxylase. J. Biol. Chem. 285, 34503-7
8. SLR-2 and JMJC-1 regulate an evolutionarily conserved stress-response network. EMBO J. 29, 727-39
9. Oxygenase-catalyzed ribosome hydroxylation occurs in prokaryotes and humans. Nat. Chem. Biol. 8, 960-962
10. Lung cancer-associated JmjC domain protein mdig suppresses formation of tri-methyl lysine 9 of histone H3. Cell Cycle 8, 2101-9
11. Structure and functional analysis of YcfD, a novel 2-oxoglutarate/Fe²⁺-dependent oxygenase involved in translational regulation in Escherichia coli. J. Mol. Biol. 426, 1898-910