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Information on EC 1.14.11.69 - [histone H3]-trimethyl-L-lysine36 demethylase and Organism(s) Homo sapiens and UniProt Accession O75164
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1.14.11.69 [histone H3]-trimethyl-L-lysine36 demethylaseIUBMB Comments
Requires iron(II). This entry describes a group of enzymes that demethylate N-methylated Lys36 residues in the tail of the histone protein H3 (H3K36). This lysine residue can exist in three methylation states (mono-, di- and trimethylated), but this group of enzymes only act on the the tri- and di-methylated forms. The enzymes are dioxygenases and act by hydroxylating the methyl group, forming an unstable hemiaminal that leaves as formaldehyde. Since trimethylation of H3K36 enhances transcription, this enzyme acts as a transcription repressor. The enzymes that possess this activity often also catalyse the activity of EC 1.14.11.66, [histone H3]-trimethyl-L-lysine9 demethylase. cf. EC 1.14.11.27, [histone H3]-dimethyl-L-lysine36 demethylase.
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Word Map
- 1.14.11.69
-
demethylation
- demethylases
- chromatin
-
jumonji
-
trimethylation
- fbxl10
-
polycomb
-
heterochromatic
- hp1a
- analysis
- medicine
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
hide(Overall reactions are displayed. Show all >>)
Synonyms
jmjc protein, jmjc demethylase, histone h3k36 demethylase, jmjd-2, h3k36 histone demethylase, rph1/kdm4, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
JMJD2A
-
KDM4A
-
JHDM3A
-
-
-
-
JMJD2A
-
-
-
-
JMJD2B
KDM4A
-
-
-
-
KDM4B
Rph1
-
-
-
-
additional information
JMJD2B
-
-
-
-
KDM4B
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
[histone H3]-N6,N6,N6-trimethyl-L-lysine36,2-oxoglutarate:oxygen oxidoreductase
Requires iron(II). This entry describes a group of enzymes that demethylate N-methylated Lys36 residues in the tail of the histone protein H3 (H3K36). This lysine residue can exist in three methylation states (mono-, di- and trimethylated), but this group of enzymes only act on the the tri- and di-methylated forms. The enzymes are dioxygenases and act by hydroxylating the methyl group, forming an unstable hemiaminal that leaves as formaldehyde. Since trimethylation of H3K36 enhances transcription, this enzyme acts as a transcription repressor. The enzymes that possess this activity often also catalyse the activity of EC 1.14.11.66, [histone H3]-trimethyl-L-lysine9 demethylase. cf. EC 1.14.11.27, [histone H3]-dimethyl-L-lysine36 demethylase.
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
a [histone H3]-N6,N6,N6-trimethyl-L-lysine36 + 2-oxoglutarate + O2
a [histone H3]-N6,N6-dimethyl-L-lysine36 + succinate + formaldehyde + CO2
-
-
-
?
ATKAARK(me3)-SAPATGGVKKPHRYRPG-GK(biotin) + 2-oxoglutarate + O2
ATKAARKSAPATGGVKKPHRYRPG-GK(biotin) + succinate + formaldehyde + CO2
usage of immunodetection for assay quantification
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 26 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 26 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
[histone H3]-N6,N6,N6-trimethyllysine36 + 2 2-oxoglutarate + 2 O2
[histone H3]-N6-methyllysine36 + 2 succinate + 2 formaldehyde + 2 CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyllysine36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyllysine36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
[histone H3]-N6,N6-dimethyllysine36 + 2-oxoglutarate + O2
[histone H3]-N6-methyllysine36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 26 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 26 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 26 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine26 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
substrate binding structure, overview
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
substrate binding structure, overview
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
additional information
?
-
JMJD2A also catalyzes the reaction of the [histone H3]-lysine-9 demethylase. JMJD2A exclusively catalyzes the demethylation of H3K9me3 and H3K36me3, converting H3K9/36me3 to H3K9/36me2 but it cannot convert H3K9/36me1 or unmethylated H3K9/K36, overview
-
-
?
additional information
?
-
bifunctional H3K9/36me3 lysine demethylase KDM4A/JMJD2A acting on Lys 9 and Lys36 of histone 3
-
-
?
additional information
?
-
JMJD2A demethylates trimethylated histone K9/K36 to di- but not mono- or unmethylated products, i.e. JMJD2A also catalyzes the reactions of EC 1.14.11.66, H3K9 trimethyl demethylase
-
-
?
additional information
?
-
bifunctional enzyme active on H3K9me3/me2 (EC 1.14.11.66) and on H3K36me3/me2
-
-
?
additional information
?
-
bifunctional KDM4A catalyzes demethylation of tri- and di-methylated forms of both histone H3 lysine 9 (H3K9me3/me2) and lysine 36 (H3K36me3/me2). Enzyme KDM4A preferentially catalyzes demethylation at Lys9 rather than Lys36 under identical conditions. Demethylation of H3K9me3 to H3K9me0 is observed on prolonged incubation of 15-residue H3K9me3 peptides
-
-
?
additional information
?
-
bifunctional KDM4A catalyzes demethylation of tri- and di-methylated forms of both histone H3 lysine 9 (H3K9me3/me2) and lysine 36 (H3K36me3/me2). Enzyme KDM4A preferentially catalyzes demethylation at Lys9 rather than Lys36 under identical conditions. Demethylation of H3K9me3 to H3K9me0 is observed on prolonged incubation of 15-residue H3K9me3 peptides
-
-
?
additional information
?
-
bifunctional KDM4A catalyzes demethylation of tri- and di-methylated forms of both histone H3 lysine 9 (H3K9me3/me2) and lysine 36 (H3K36me3/me2). Enzyme KDM4A preferentially catalyzes demethylation at Lys9 rather than Lys36 under identical conditions. Demethylation of H3K9me3 to H3K9me0 is observed on prolonged incubation of 15-residue H3K9me3 peptides
-
-
?
additional information
?
-
enzyme additionally demethylates H3K9me3, reaction of EC 1.14.11.66
-
-
?
additional information
?
-
human enzyme JMJD2A (jumonji domain containing 2A) is selective towards tri- and dimethylated histone H3 lysyl residues 9 and 36 (H3K9me3/me2 and H3K36me3/me2), it discriminates between methylation states and achieves sequence selectivity for H3K9. Structures reveal a lysyl-binding pocket in which substrates are bound in distinct bent conformations involving the Zn2+-binding site
-
-
?
additional information
?
-
human JMJD2A exhibits dual specificity for the trimethylated and, to a lesser extent, the dimethylated forms of H3K9 and H3K36, with an approximately fivefold preference in specificity for the H3K9me3 substrate due to a higher KM value for the H3K36me3 peptide, suggesting that JMJD2A preferentially recognizes the H3K9me3 site
-
-
?
additional information
?
-
JHDM3A removes the me3 group from modified H3 lysine 9 (H3K9) and H3 lysine 36 (H3K36)
-
-
?
additional information
?
-
JMJD2A is a JmjC histone demethylase (HDM) that catalyzes the demethylation of di- and trimethylated Lys9 and Lys36 in histone H3 (H3K9me2/3 and H3K36me2/3). Trimethylated Lys9 is the best substrate. JMJD2A preferentially demethylates trimethylated substrates. Histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated epsilon-ammonium cation is coordinated within a methylammonium-binding pocket through carbon-oxygen hydrogen bonds that position one of the zeta-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation. Analysis of the H3K9me3 or H3K36me3 peptide binding structure to the enzyme, overview
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates. Usage of a formaldehyde dehydrogenase (FDH) enzyme-coupled demethylase activity assay
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 and H3K36me3/me2 substrates. The cellular activity of recombinant KDM4A against its primary substrate, H3K9me3, displays a graded response to depleting oxygen concentrations in line with the data obtained using isolated protein
-
-
?
additional information
?
-
bifunctional KDM4A catalyzes demethylation of tri- and di-methylated forms of both histone H3 lysine 9 (H3K9me3/me2) and lysine 36 (H3K36me3/me2). Enzyme KDM4B preferentially catalyzes demethylation at Lys9 rather than Lys36 under identical conditions. Demethylation of H3K9me3 to H3K9me0 is observed on prolonged incubation of 15-residue H3K9me3 peptides
-
-
?
additional information
?
-
bifunctional KDM4A catalyzes demethylation of tri- and di-methylated forms of both histone H3 lysine 9 (H3K9me3/me2) and lysine 36 (H3K36me3/me2). Enzyme KDM4B preferentially catalyzes demethylation at Lys9 rather than Lys36 under identical conditions. Demethylation of H3K9me3 to H3K9me0 is observed on prolonged incubation of 15-residue H3K9me3 peptides
-
-
?
additional information
?
-
bifunctional KDM4A catalyzes demethylation of tri- and di-methylated forms of both histone H3 lysine 9 (H3K9me3/me2) and lysine 36 (H3K36me3/me2). Enzyme KDM4B preferentially catalyzes demethylation at Lys9 rather than Lys36 under identical conditions. Demethylation of H3K9me3 to H3K9me0 is observed on prolonged incubation of 15-residue H3K9me3 peptides
-
-
?
additional information
?
-
bifunctional KDM4A catalyzes demethylation of tri- and di-methylated forms of both histone H3 lysine 9 (H3K9me3/me2) and lysine 36 (H3K36me3/me2). Enzyme KDM4C preferentially catalyzes demethylation at Lys9 rather than Lys36 under identical conditions. Demethylation of H3K9me3 to H3K9me0 is observed on prolonged incubation of 15-residue H3K9me3 peptides
-
-
?
additional information
?
-
bifunctional KDM4A catalyzes demethylation of tri- and di-methylated forms of both histone H3 lysine 9 (H3K9me3/me2) and lysine 36 (H3K36me3/me2). Enzyme KDM4C preferentially catalyzes demethylation at Lys9 rather than Lys36 under identical conditions. Demethylation of H3K9me3 to H3K9me0 is observed on prolonged incubation of 15-residue H3K9me3 peptides
-
-
?
additional information
?
-
bifunctional KDM4A catalyzes demethylation of tri- and di-methylated forms of both histone H3 lysine 9 (H3K9me3/me2) and lysine 36 (H3K36me3/me2). Enzyme KDM4C preferentially catalyzes demethylation at Lys9 rather than Lys36 under identical conditions. Demethylation of H3K9me3 to H3K9me0 is observed on prolonged incubation of 15-residue H3K9me3 peptides
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates
-
-
?
additional information
?
-
the bifunctional enzyme is active on H3K9me3/me2 (EC 1.14.11.66) and H3K36me3/me2 substrates
-
-
?
additional information
?
-
the bifunctional enzyme specifically demethylates Lys9 and Lys36 residues of histone H3 (EC 1.14.11.66)
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
a [histone H3]-N6,N6,N6-trimethyl-L-lysine36 + 2-oxoglutarate + O2
a [histone H3]-N6,N6-dimethyl-L-lysine36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 26 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 26 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
[histone H3]-N6,N6,N6-trimethyl-L-lysine 26 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 26 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
additional information
?
-
JMJD2A demethylates trimethylated histone K9/K36 to di- but not mono- or unmethylated products, i.e. JMJD2A also catalyzes the reactions of EC 1.14.11.66, H3K9 trimethyl demethylase
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6,N6-dimethyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
[histone H3]-N6,N6-dimethyl-L-lysine 36 + 2-oxoglutarate + O2
[histone H3]-N6-methyl-L-lysine 36 + succinate + formaldehyde + CO2
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
alteration of multiple H3 methylation marks by KDM4A at different oxygen concentrations, overview
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
additional information
structures reveal a lysyl-binding pocket in which substrates are bound in distinct bent conformations involving the Zn-binding site
Fe2+
the mechanism for achieving methylation state selectivity involves the orientation of the substrate methyl groups towards a ferryl intermediate
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
3-[hydroxy-[5-[[(1R)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-5-oxo-pentanoyl]amino]propanoic acid
-
3-[hydroxy-[5-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-5-oxo-pentanoyl]amino]propanoic acid
-
3-[hydroxy-[7-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-7-oxo-heptanoyl]amino]propanoic acid
-
3-[hydroxy-[8-[[(1R)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
-
3-[hydroxy-[8-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
-
3-[hydroxy-[8-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
-
8-(4-(2-(4-(3,5-dichlorophenyl)piperidin-1-yl)ethyl)-1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one
-
8-(hydroxyamino)-N-[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]-8-oxo-octanamide
-
Co2+
has an activating on multiple histone modifications at the global level. Cobalt ions significantly increase global histone H3K4me3, H3K9me2, H3K9me3, H3K27me3 and H3K36me3, as well as uH2A and uH2B and decreases acetylation at histone H4 (AcH4) in vivo. Cobalt ions increase H3K9me3 and H3K36me3 by inhibiting histone demethylation process in vivo. And cobalt ions directly inhibit demethylase activity of JMJD2A in vitro. Cobalt ions do not increase the level of uH2A in the in vitro histone ubiquitinating assay and inhibit histone-deubiquitinating enzyme activity in vitro
H2O2
loss of KDM4A activity in hypoxia resulting in changes to global histone lysine methylation
methyl (2S)-2-[[4-[3-(hydroxyamino)-3-oxo-propyl]benzoyl]amino]-3-(4-phenylphenyl)propanoate
-
methyl (2S)-2-[[7-(hydroxyamino)-7-oxo-heptanoyl]amino]-3-(4-phenylphenyl)propanoate
-
methyl (2S)-2-[[7-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-7-oxo-heptanoyl]amino]-3-(4-phenylphenyl)propanoate
-
methyl (2S)-2-[[8-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-8-oxo-octanoyl]amino]-3-(4-phenylphenyl)propanoate
-
methyl (S)-3-(2'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
methyl (S)-3-(3'-cyano-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
methyl (S)-3-(3'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
methyl (S)-3-(4'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
methyl (S)-3-(4'-cyano-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
methyl (S)-3-(4'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
methyl (S)-3-(6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
methyl (S)-3-([1,1'-biphenyl]-4-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
methyl 3-(3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
-
methyl 3-[hydroxy-[8-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoate
-
N-[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]heptanamide
-
N1-((3'-chloro-6-methoxy-[1,1'-biphenyl]-3-yl)methyl)-N8-hydroxyoctanediamide
-
N1-(2-(3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)ethyl)-N8-hydroxyoctanediamide
-
N1-(2-(3'-chloro-6-methoxy-[1,1'-biphenyl]-3-yl)ethyl)-N8-hydroxyoctanediamide
-
SW55
a hydroxamate-based histone deacetylase (HDAC) inhibitor, slight inhibition
tert-butyl (2S)-2-[[8-(hydroxyamino)-8-oxo-octanoyl]amino]-3-(4-phenylphenyl)propanoate
-
tert-butyl (2S)-2-[[8-(hydroxyamino)-8-oxo-octanoyl]amino]-3-phenyl-propanoate
-
additional information
4-biphenylalanine- and 3-phenyltyrosine-derived hydroxamic acids are inhibitors of the JumonjiC-domain-containing histone demethylase KDM4A, synthesis and chemical modifications on the lead structure and biochemical evaluation, structure-activity relationships, overview. For KDM4A inhibition, the best compounds are those bearing a biphenylalanine cap (both configurations) with an additional hydroxamic acid moiety, a C8 alkyl chain as spacer, and an N-alkylated warhead for the selectivity against hydroxamate-based histone deacetylases, HDACs, methyl 3-[hydroxy-[8-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoate and 3-[hydroxy-[8-[[(1R)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid. Effect of inhibitors compounds methyl (2S)-2-[[7-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-7-oxo-heptanoyl]amino]-3-(4-phenylphenyl)propanoate, 3-[hydroxy-[7-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-7-oxo-heptanoyl]amino]propanoic acid, methyl (2S)-2-[[8-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-8-oxo-octanoyl]amino]-3-(4-phenylphenyl)propanoate, and 3-[hydroxy-[8-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid on on cell proliferation of KYSE-150 and HL-60 cells. Cell-permeable derivatives clearly show a demethylase-inhibition-dependent antiproliferative effect against HL-60 human promyelocytic leukemia cells
-
additional information
structures of JMJD2A-Ni(II)-Zn(II) inhibitor complexes bound to tri-, di- and monomethyl forms of H3K9 and the trimethyl form of H3K36, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
fisetin
fisetin induces DNA damage via critical transcription factor RFXAP/KDM4A-dependent histone H3K36 demethylation, thus causing inhibition of proliferation in pancreatic adenocarcinoma (PDAC). Fisetin inhibits cell proliferation and induces DNA damage and S-phase arrest in PDAC. Expression of RFXAP and other DNA-damage response genes is upregulated by fisetin. RFXAP targets KDM4A. Overexpression of RFXAP upregulates KDM4A and attenuates methylation of H3K36, impairing DNA repair and enhancing the DNA damage induced by fisetin
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.32
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36
pH 7.3, 37°C, recombinant enzyme
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000217
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36
pH 7.3, 37°C, recombinant enzyme
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00068
[histone H3]-N6,N6,N6-trimethyl-L-lysine 36
pH 7.3, 37°C, recombinant enzyme
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.037
2-(2-((chroman-6-ylmethyl)amino)pyrimidin-4-yl)isonicotinic acid
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.003
3-(9-(dimethylamino)-N-hydroxynonanamido)propanoic acid
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.2
3-[hydroxy-[5-[[(1R)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-5-oxo-pentanoyl]amino]propanoic acid
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0703
3-[hydroxy-[5-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-5-oxo-pentanoyl]amino]propanoic acid
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0606
3-[hydroxy-[7-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-7-oxo-heptanoyl]amino]propanoic acid
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0068
3-[hydroxy-[8-[[(1R)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0136
3-[hydroxy-[8-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0371
3-[hydroxy-[8-[[(1S)-2-methoxy-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoic acid
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0085
8-(hydroxyamino)-N-[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]-8-oxo-octanamide
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0258
methyl (2S)-2-[[4-[3-(hydroxyamino)-3-oxo-propyl]benzoyl]amino]-3-(4-phenylphenyl)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0706
methyl (2S)-2-[[7-(hydroxyamino)-7-oxo-heptanoyl]amino]-3-(4-phenylphenyl)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.056
methyl (2S)-2-[[7-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-7-oxo-heptanoyl]amino]-3-(4-phenylphenyl)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0171
methyl (2S)-2-[[8-[hydroxy-(3-methoxy-3-oxo-propyl)amino]-8-oxo-octanoyl]amino]-3-(4-phenylphenyl)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0563
methyl (S)-3-(2'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0476
methyl (S)-3-(3'-cyano-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.029
methyl (S)-3-(3'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0483
methyl (S)-3-(4'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0548
methyl (S)-3-(4'-cyano-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0522
methyl (S)-3-(4'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0939
methyl (S)-3-(6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0254
methyl (S)-3-([1,1'-biphenyl]-4-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0276
methyl 3-(3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)-2-(8-(hydroxyamino)-8-oxooctanamido)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0068
methyl 3-[hydroxy-[8-[[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]amino]-8-oxo-octanoyl]amino]propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.2
N-[(1S)-2-(hydroxyamino)-2-oxo-1-[(4-phenylphenyl)methyl]ethyl]heptanamide
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0145
N1-((3'-chloro-6-methoxy-[1,1'-biphenyl]-3-yl)methyl)-N8-hydroxyoctanediamide
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0188
N1-(2-(3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)ethyl)-N8-hydroxyoctanediamide
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0166
N1-(2-(3'-chloro-6-methoxy-[1,1'-biphenyl]-3-yl)ethyl)-N8-hydroxyoctanediamide
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
0.0143
tert-butyl (2S)-2-[[8-(hydroxyamino)-8-oxo-octanoyl]amino]-3-(4-phenylphenyl)propanoate
Homo sapiens
pH 7.5, 37°C, recombinant enzyme
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
JMJD2B expression profile in gastric cancer, overview
KDM4A is amplified and overexpressed in cancer cells of several tumor types
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
isozyme KDM4C is associated with chromatin during mitosis, residue R919 on the proximal Tudor domains of KDM4C is critical for its association with chromatin during mitosis. KDM4C protein is localized to mitotic chromatin from prometaphase to telophase
additional information
additional information
while KDM4C is associated with mitotic chromatin, KDM4A-B proteins are excluded from chromatin throughout prometaphase-telophase
-
additional information
while KDM4C is associated with mitotic chromatin, KDM4A-B proteins are excluded from chromatin throughout prometaphase-telophase
-
additional information
while KDM4C is associated with mitotic chromatin, KDM4A-B proteins are excluded from chromatin throughout prometaphase-telophase
-
additional information
while KDM4C is associated with mitotic chromatin, KDM4A-B proteins are excluded from chromatin throughout prometaphase-telophase
-
additional information
while KDM4C is associated with mitotic chromatin, KDM4A-B proteins are excluded from chromatin throughout prometaphase-telophase
-
additional information
while KDM4C is associated with mitotic chromatin, KDM4A-B proteins are excluded from chromatin throughout prometaphase-telophase
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
evolution
malfunction
physiological function
additional information
evolution
the enzyme belongs to the KDM2-8 family, KDM4 (also known as JMJD2) subfamily, which divided into five isoforms A-E
evolution
the enzyme belongs to the KDM4/JmjC demethylase histone demethylase family. The selectivity of KDM4 enzymes is determined by multiple interactions within the catalytic domain but outside the active site. All KDM4 subfamily members have highly conserved residues lining the methylammonium-binding pocket. The exceptions are Ser288A/Ser-289B/Ser290C and Thr289A/Thr290B/Thr291C in KDM4A, B, and C, which are substituted by Ala287D/Ala289E/Ala286F and Ile288D/Ile290E/Ile287F in KDM4D-F, respectively. Evolutionary analysis of the KDM4 demethylase subfamily
evolution
the human KDM4 family consists of four members, KDM4A-D (also known as JMJD2A-D). These enzymes specifically catalyze the demethylation of H3K9me3/me2, H3K36me2/me3 and H1.4K26me2/me3 in a Fe2+ and 2-oxoglutarate-dependent manner. Besides the catalytic JmjC domain, KDM4 demethylases contain the JmjN domain, which is also required for the demethylase activity. In addition, all KDM4 members, except the shortest KDM4D protein, contain two Plant homeodomain (PHD) and two Tudor domains. PHD and Tudor domains are not required for KDM4 enzymatic activity. Gene KDM4D is Y chromosome-encoded and a truncated enzyme variant compared to KDM4A-C
malfunction
dysregulated expression of KDM4A-D family promotes chromosomal instabilities
malfunction
KDM4A/JMJD2A overexpression leads to localized copy gain of 1q12, 1q21, and Xq13.1 without global chromosome instability, KDM4A-amplified tumors have increased copy gains for these same regions. 1q12h copy gain occurs within a single cell cycle, requires S phase, and is not stable but is regenerated each cell division. Sites with increased copy number are rereplicated and have increased KDM4A, MCM, and DNA polymerase occupancy. Suv39h1/KMT1A or HP1gamma overexpression suppresses the copy gain, whereas H3K9/K36 methylation interference promotes gain. Overexpression of a chromatin modifier results in site-specific copy gains
malfunction
mutations of the residues comprising the methylammonium-binding pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2
malfunction
overexpression of the histone lysine demethylase KDM4A is related to the pathology of several human cancers
malfunction
Pim1 knockdown and P21(WAF1/Cip1) overexpression fully abrogates the oncogenic function of JMJD2A. A 39KD JMJD2A transcript, JMJD2ADELTA, is significantly increased in JMJD2A or miR372 overexpressing Hep3B cell line
metabolism
exposure to Co2+ increases gene repression markers (H3K9me3, H3K27me3, H3K36me3, H3K9me2, uH2A and lack of AcH4), as well as gene activation markers (H3K4me3 and uH2B) in both A549 and Beas-2B cells. Cobalt ions increase H3K9me3 and H3K36me3 by inhibiting histone demethylation process in vivo
metabolism
KDM4A possesses the potential to act as an oxygen sensor in the context of epigenetic regulation
metabolism
many JmjC HDMs appear to function in the context of large multimeric complexes that govern their localization, transcriptional functions, and potentially their substrate specificity. In the case of certain JmjC enzymes, these complexes appear to be critical in conferring specificity for nucleosomal substrates
metabolism
the FBXO22-containing SCF E3 ubiquitin ligase complex controls the activity of KDM4A by targeting it for proteasomal turnover in a ubiquitin K48-dependent manner. FBXO22 functions as a receptor for KDM4A by recognizing its catalytic JmjN/JmjC domains via its intracellular signal transduction domain. Modulation of FBXO22 levels leads to increased or decreased levels of KDM4A, respectively. Changes in KDM4A abundance correlate with alterations in histone H3 lysine 9 and 36 methylation levels, and transcription of a KDM4A target gene, ASCL2
physiological function
H3K9me3 demethylase KDM4A/JMJD2A is able to increase accessibility and alter the replication timing at specific heterochromatic regions. KDM4A overexpression promotes copy gain of 1q12, 1q21, and Xq13.1 in cancer cells and results in site-specific copy gain of regions amplified in human tumors. These copy gains are not stably inherited but are generated transiently in each subsequent S phase and cleared by late G2. KDM4A is the only KDM4 family member that generated the gains in a catalytically dependent manner, copy gains are antagonized by coexpression of Suv39h1/KMT1A or HP1gamma, and promoted by H3K9 or H3K36 methylation interference. KDM4A associates with replication machinery and promotes rereplication of 1q12. KDM4A overexpression promotes chromatin state changes and recruitment of replication machinery. KDM4A-dependent 1q12h copy gain requires catalytic activity and Tudor domains, the KDM4A catalytic domain alone is insufficient to generate 1q12h gain
physiological function
JMJD2A accelerates malignant progression of liver cancer cells in vitro and in vivo. Mechanistically, JMJD2A promotes the expression and mature of pre-miR372 epigenetically. Notably, miR372 blocks the editing of 13th exon-introns-14th exon and forms a novel transcript (JMJD2ADELTA) of JMJD2A. Enzyme JMJD2A is overexpressed in cancer and inhibits repair of DNA damage by reducing homologous recombination repair. Histone H3K36 trimethylation (H3K36me3) is associated with carcinogenesis. Histone H3 demethylase JMJD2A promotes growth of liver cancer cells, via Pim1-ppRB1-CDK2-CycinE-C-myc pathway, through upregulating miR372, JMJD2A enhances miR372 expression epigenetically, mechanism, overview. In particular, JMJD2A inhibits P21 (WAF1/Cip1) expression by decreasing H3K9me3 dependent on JMJD2ADELTA. JMJD2A enhances Pim1 transcription by suppressing P21(WAF1/Cip1) involving altered histone H3 lysine 9 methylation. Furthermore, through increasing the expression of Pim1, JMJD2A facilitates the interaction among pRB, CDK2 and CyclinE which prompts the transcription and translation of oncogenic C-myc. JMJD2A may trigger the demethylation of Pim1
physiological function
JMJD2A is implicated in transcriptional silencing and is associated with the retinoblastoma protein, class I HDACs, and the nuclear corepressor N-CoR. JMJD2A and its paralogue JMJD2D associate with the androgen receptor (AR) to upregulate the expression of AR-dependent genes. The transcriptional functions of JMJD2 enzymes appear to be context-dependent
physiological function
KDM4A overexpression promotes chromatin state changes and recruitment of replication machinery and leads to localized copy gain of cytogenetic bands 1q12, 1q21, and Xq13.1 without global chromosome instability. KDM4A-amplified tumors have increased copy gains for these same regions. 1q12h copy gain occurs within a single cell cycle, requires S phase and is not stable but regenerated each cell division. Sites with increased copy number are rereplicated and have increased KDM4A, MCM and DNA polymerase occupancy. Suv39h1/KMT1A or HP1gamma overexpression suppresses the copy gain, while H3K9/K36 methylation interference promotes gain
physiological function
overexpression of JHDM3A abrogates recruitment of HP1 (heterochromatin protein 1) to heterochromatin. Knockdown of JHDM3A leads to increased levels of H3K9 methylation and upregulation of JHDM3A target gene ASCL2
physiological function
overexpression of JMJD2A reduces H3-K9/K36 trimethylation levels in cultured cells
physiological function
reducing H3K36me3 levels by overexpressing KDM4A reduces homologous recombination repair events. Tumor suppressor SETD2 is also required for homologous recombination repair events
physiological function
the histone lysine demethylase KDM4A regulates H3K9 and H3K36 methylation states
physiological function
the JmjC histone lysine demethylases (KDMs) are epigenetic regulators involved in the removal of methyl groups from post-translationally modified lysyl residues within histone tails, modulating gene transcription
physiological function
various types of human cancers exhibit amplification or deletion of KDM4A-D members, which selectively demethylate H3K9 and H3K36, thus implicating their activity in promoting carcinogenesis
physiological function
JMJD2A displays higher expression in glioma tissues than that in normal brain tissues and lower levels of H3K9me3/H3K36me3 are found in glioma tissues. Knockdown of JMJD2A expression attenuates the growth and colony formation in glioma cell lines U251, T98G, and U87MG, whereas JMJD2A overexpression results in opposing effects. JMJD2A knockdown reduces the growth of glioma T98G cells in vivo. JMJD2A activates the Akt-mTOR pathway and promotes protein synthesis in glioma cells via promoting phosphoinositide-dependent kinase-1 expression
evolution
the enzyme belongs to the KDM4/JmjC demethylase histone demethylase family. The selectivity of KDM4 enzymes is determined by multiple interactions within the catalytic domain but outside the active site. Evolutionary analysis of the KDM4 demethylase subfamily
evolution
the human KDM4 family consists of four members, KDM4A-D (also known as JMJD2A-D). These enzymes specifically catalyze the demethylation of H3K9me3/me2, H3K36me2/me3 and H1.4K26me2/me3 in a Fe2+ and 2-oxoglutarate-dependent manner. Besides the catalytic JmjC domain, KDM4 demethylases contain the JmjN domain, which is also required for the demethylase activity. In addition, all KDM4 members, except the shortest KDM4D protein, contain two Plant homeodomain (PHD) and two Tudor domains. Gene KDM4D is Y chromosome-encoded and a truncated enzyme variant compared to KDM4A-C
malfunction
dysregulated expression of KDM4A-D family promotes chromosomal instabilities. Dysregulation of KDM4C expression promotes mitotic chromosome missegregation. KDM4B-C members are overexpressed in several types of human cancer and its depletion impairs cancer cell proliferation
malfunction
dysregulated expression of KDM4A-D family promotes chromosomal instabilities. KDM4B-C members are overexpressed in several types of human cancer and its depletion impairs cancer cell proliferation
malfunction
knocking down JMJD2B expression by siRNA in gastric and other cancer cells inhibits cell proliferation and/or induces apoptosis and elevates the expression of p53 and p21CIP1 proteins, mechanism of JMJD2B inhibition, overview. The enhanced p53 expression results from activation of the DNA damage response pathway
physiological function
histone demethylase JMJD2B regulates chromatin structure or gene expression by removing methyl residues from trimethylated lysine 9 on histone H3 and is required for tumor cell proliferation and survival in vitro and in vivo, and is overexpressed in gastric cancer
physiological function
-
anticancer agent nutlin kills MDM2-amplified cancer cells by altering histone methylation in an MDM2 proto-oncogene-dependent manner. MDM2 amplification increases histone methylation in nutlin-treated cells by causing depletion of histone demethylase JMJD2B. JMJD2B knockdown or inhibition increases H3K9/K36me3 levels, decreases ATG gene expression and autophagy, and sensitizes MDM2-nonamplified cells to apoptosis
physiological function
-
papillomaviruses DNA is histone-associated in infected cells. Reducing H3K36me3 by overexpression of KDM4A blocks productive viral replication. H3K36me3 is enriched on the 3' end of the early region of the high-risk papillomavirus HPV31 genome in a SETD2-dependent manner
physiological function
various types of human cancers exhibit amplification or deletion of KDM4A-D members, which selectively demethylate H3K9 and H3K36, thus implicating their activity in promoting carcinogenesis
additional information
cellular demethylase activity of KDM4A demonstrates a graded response to oxygen concentration in U2OS cells. Analysis of the H3K27me3 (cf. EC 1.14.11.68) mark shows loss of this mark upon overexpression of KDM4A in normoxia, with a graded response to oxygen similar to that seen for H3K9me3, although less-pronounced. H3K27me3 is not a canonical substrate for KDM4A, hence, loss of this mark cannot be directly attributed to catalytic KDM4A activity. Effect of oxygen availability on the activity of the KDM4 subfamily member KDM4A, overview. A high level of O2 sensitivity both with isolated protein and in cells is observed
additional information
enzyme structure-function relationships and substrate selectivity, comparisons of KDM4 enzymes, overview
additional information
enzyme structure-function relationships and substrate selectivity, comparisons of KDM4 enzymes, overview
additional information
enzyme structure-function relationships and substrate selectivity, comparisons of KDM4 enzymes, overview
additional information
in H3K9me3- and H3K36me3-enzyme complexes, the peptides bind in the same directionality within the substrate binding cleft of JMJD2A, depositing the trimethyllysines into the active site. The majority of the interactions between the enzyme and H3 peptides involve hydrogen bond and van der Waals interactions with the backbone atoms in the substrates. The residues N-terminal to the trimethyllysines adopt a similar beta-strand-like conformation, while the C-terminal residues in the peptides adopt distinct binding modes. Mono-, di-, and trimethyllysines bind within a methylammonium binding pocket adjacent to the Fe(II) and 2-oxoglutarate binding sites in JMJD2A. This pocket is lined with an array of oxygen atoms that participate in direct contacts with zeta-methyl groups of the trimethylated substrate. Structure-activity analysis, overview
additional information
interaction between JMJD2A and substrate peptides largely involves the main chains of the enzyme and the peptide. The peptide-binding specificity is primarily determined by the primary structure of the peptide, which explains the specificity of JMJD2A for methylated H3K9 and H3K36 instead of other methylated residues such as H3K27. The specificity for a particular methyl group is affected by multiple factors, such as space and the electrostatic environment in the catalytic center of the enzyme. Mechanisms and specificity of histone demethylation, overview. Residues Q86, N88, D135, and Y175 are involved in the interaction with the peptide, whereas residues Y177, N290, S288, and T289 are involved in methyl group binding. K241 is proposed to recruit the O2 molecule into the catalytic center. Glycine residues at +3 or +4 in the substrate are essential for substrate specificity
additional information
residue S288 modulates the methylation-state specificities of JMJD2 enzymes and other trimethyllysine-specific JmjC HDMs. The mechanisms by which JMJD2A discriminates against the demethylation of H3K4me and H4K20me. An alignment of the H3K4, H3K9, H3K36 and H4K20 methylation sites reveals substantial sequence diversity among the methylation motifs. The methylammonium-binding pocket is composed of the carbonyl oxygen of Gly170, the hydroxyl groups of Tyr177 and Ser288, and the carboxylate side chain of Glu190. Active site site structure with bound substrate, overview
additional information
the mechanism for achieving methylation state selectivity involves the orientation of the substrate methyl groups towards a ferryl intermediate. Active site structure and mechanism of JMJD2A, overview
additional information
enzyme structure-function relationships and substrate selectivity, comparisons of KDM4 enzymes, overview
additional information
enzyme structure-function relationships and substrate selectivity, comparisons of KDM4 enzymes, overview
additional information
enzyme structure-function relationships and substrate selectivity, comparisons of KDM4 enzymes, overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). KDM4A_HUMAN
1064
0
120662
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure determinations of JMJD2A in complex with histone H3 peptides bearing different methylated forms of K9 and K36
purified JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides, vapor diffusion method, from 0.2 M sodium/potassium phosphate, pH 6.5, and 20% w/v PEG 3350, at 4°C, and by microseeding from 12% w/v PEG monomethyl ether 5000 and 0.1 M HEPES, pH 7.0, X-ray diffraction structure determination and analysis at 2.05-2.30 A resolution
purified recombinant enzyme in complex with substrate peptides, by vapour diffusion at 4°C from 0.1 M citrate, pH 5.5, 20% PEG 3350 and 4 mM NiCl2, X-ray diffraction structure determination and analysis at 2.1 A resolution
purified recombinant JMJD2A catalytic core complexed with methylated H3K36 peptide substrates (trimethylated H3K36 peptide (H3K36me3) or a monomethylated H3K36 peptide (H3K36me)) in the presence of Fe(II) and N-oxalylglycine, vapor diffusion method at 4°C against a solution containing 200 mM MgCl2, 100 mM Tris, pH 8.5, and 13-15% PEG 5000, X-ray diffraction structure determination and analysis at 2.0 A resolution
structures of the JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides. The histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated epsilon-ammonium cation is coordinated within a methylammonium-binding pocket through carbonoxygen hydrogen bonds that position one of the theta-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation
purified recombinant enzyme in complex with inhibitor, sitting drop vapor diffusion method, mixing of 7 mg/ml protein and 2 mM N-oxalylglycine with well solution, containing 25% v/v PEG 3350, 0.2 M sodium nitrate, 0.1 M bis-tris propane, pH 6.5, 5% v/v ethylene glycol, 0.01 M NiCl2, in a 2:1 ratio, 4°C, X-ray diffraction structure determination and analysis at 2.55 A resolution
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D191A
site-directed mutagenesis, the mutant shows about 95%reduced activity with H3K9me3 compared to wild-type, and no activity with H3K36me3
N290A
site-directed mutagenesis, the mutant shows no activity with H3K36me3 and almost no activity with H3K9me3
N290D
site-directed mutagenesis, the mutant shows about 98%reduced activity with H3K9me3 compared to wild-type, and no activity with H3K36me3
S288A
Y175F
site-directed mutagenesis, the mutant shows about 90%reduced activity with H3K9me3 compared to wild-type, and no activity with H3K36me3
Y177F
site-directed mutagenesis, the mutant shows about 90%reduced activity with H3K9me3 compared to wild-type, and no activity with H3K36me3
R919D
site-directed mutagenesis, the mutant is not associated with mitotic chromatin in contrast to the wild-type enzyme
S198M
site-directed mutagenesis, a KDM4C demethylase dead mutant
additional information
S288A
mutations of the residues comprising the methylammonium-binding pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2
additional information
enzyme engineering and swapping of the C-terminus region containing the distal Tudor domain between isozymes KDM4C and KDM4A, construction of diverse chimeric enzyme mutants, overview. Chimera5, which encodes the first 934 amino acids of KDM4C fused with the last 129 amino acid containing the distal Tudor domain of KDM4A, is excluded from mitotic chromatin. On the other hand, chimera6 that encodes the first 954 amino acids of KDM4A fused to 101 amino acids of KDM4C, which includes its distal Tudor domain, remains excluded from chromatin. The C-terminus of KDM4C containing the distal Tudor domain is essential but not sufficient for its mitotic chromatin localization
additional information
enzyme engineering and swapping of the C-terminus region containing the distal Tudor domain between isozymes KDM4C and KDM4A, construction of diverse chimeric enzyme mutants, overview. Chimera5, which encodes the first 934 amino acids of KDM4C fused with the last 129 amino acid containing the distal Tudor domain of KDM4A, is excluded from mitotic chromatin. On the other hand, chimera6 that encodes the first 954 amino acids of KDM4A fused to 101 amino acids of KDM4C, which includes its distal Tudor domain, remains excluded from chromatin. The C-terminus of KDM4C containing the distal Tudor domain is essential but not sufficient for its mitotic chromatin localization
additional information
enzyme engineering and swapping of the C-terminus region containing the distal Tudor domain between isozymes KDM4C and KDM4A, construction of diverse chimeric enzyme mutants, overview. Chimera5, which encodes the first 934 amino acids of KDM4C fused with the last 129 amino acid containing the distal Tudor domain of KDM4A, is excluded from mitotic chromatin. On the other hand, chimera6 that encodes the first 954 amino acids of KDM4A fused to 101 amino acids of KDM4C, which includes its distal Tudor domain, remains excluded from chromatin. The C-terminus of KDM4C containing the distal Tudor domain is essential but not sufficient for its mitotic chromatin localization
additional information
introduction of a di-glycine motif at the +3 to +4 positions of the H3K27 sequence, a site which shares sequence homology with the H3K9 sequence, enables JMJD2A to efficiently demethylate H3K27me3, cf. EC 1.14.11.68
additional information
JMJD2A knockout or overexpression in Hep-3B cells. Construction of JMJD2ADELTA mutant. A 39KD JMJD2A transcript, JMJD2ADELTA, is significantly increased in JMJD2A or miR372 overexpressing Hep3B cell line
additional information
transposition of the Ala-Pro motif of H3K27 to AARK(me3)SPAAT, to mimic the proline position in H3K36, resulted in no detectable activity
additional information
enzyme engineering and swapping of the C-terminus region containing the distal Tudor domain between isozymes KDM4C and KDM4A, construction of diverse chimeric enzyme mutants, overview. Chimera5, which encodes the first 934 amino acids of KDM4C fused with the last 129 amino acid containing the distal Tudor domain of KDM4A, is excluded from mitotic chromatin. On the other hand, chimera6 that encodes the first 954 amino acids of KDM4A fused to 101 amino acids of KDM4C, which includes its distal Tudor domain, remains excluded from chromatin. The C-terminus of KDM4C containing the distal Tudor domain is essential but not sufficient for its mitotic chromatin localization. EGFP-KDM4CRDTF/DNLY mutant is excluded from mitotic chromatin. For isozyme knockout, U2OS cells are transfected with KDM4B-C siRNA sequences
additional information
enzyme engineering and swapping of the C-terminus region containing the distal Tudor domain between isozymes KDM4C and KDM4A, construction of diverse chimeric enzyme mutants, overview. Chimera5, which encodes the first 934 amino acids of KDM4C fused with the last 129 amino acid containing the distal Tudor domain of KDM4A, is excluded from mitotic chromatin. On the other hand, chimera6 that encodes the first 954 amino acids of KDM4A fused to 101 amino acids of KDM4C, which includes its distal Tudor domain, remains excluded from chromatin. The C-terminus of KDM4C containing the distal Tudor domain is essential but not sufficient for its mitotic chromatin localization. EGFP-KDM4CRDTF/DNLY mutant is excluded from mitotic chromatin. For isozyme knockout, U2OS cells are transfected with KDM4B-C siRNA sequences
additional information
enzyme engineering and swapping of the C-terminus region containing the distal Tudor domain between isozymes KDM4C and KDM4A, construction of diverse chimeric enzyme mutants, overview. Chimera5, which encodes the first 934 amino acids of KDM4C fused with the last 129 amino acid containing the distal Tudor domain of KDM4A, is excluded from mitotic chromatin. On the other hand, chimera6 that encodes the first 954 amino acids of KDM4A fused to 101 amino acids of KDM4C, which includes its distal Tudor domain, remains excluded from chromatin. The C-terminus of KDM4C containing the distal Tudor domain is essential but not sufficient for its mitotic chromatin localization. EGFP-KDM4CRDTF/DNLY mutant is excluded from mitotic chromatin. For isozyme knockout, U2OS cells are transfected with KDM4B-C siRNA sequences
additional information
Jmjd2b knockdown by siRNA, leading to induction of p53 via activation of the DNA damage response pathway. p53 Inhibition significantly restored the clonogenic potential of AGS and HeLa cells treated with JMJD2B siRNA. Increased apoptosis in BGC-823 and HeLa cells but not AGS cells with JMJD2B siRNA knockdown. AGS cells are arrested at the G1 phase, but BGC-823 and HeLa cells are arrested at the S phase
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged enzyme from Escherichia coli strain Rosetta 2 (DE3) by nickel affinity chromatography and gel filtration
recombinant His-tagged KDM4A residues 1-359 from Escherichia coli strain BL21 Codon-Plus-Ril by nickel affinity chromatography to over 90% purity
recombinant N-terminally His-tagged enzyme from Escherichia coli by nickel affinity chromatography, gel filtration, and anion exchange chromatography
recombinant N-terminally His-tagged KDM4A catalytic domain from Escherichia coli
recombinant N-terminally His6-tagged truncated KDM4A1-359 from Escherichia coli strain BL21(DE3) by nickel affinity chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene KDM4A, phylogenetic analysis, recombinant expression of N-terminally His-tagged KDM4A catalytic domain in Escherichia coli
gene KDM4A, recombinant expression of EGFP-tagged full-length and truncated enzymes versions in U2-O2 cells
gene KDM4A, recombinant expression of FLAG-tagged JMJD2A in Spodoptera frugiperda Sf9 cells
gene KDM4A, recombinant expression of His-tagged enzyme in Escherichia coli strain Rosetta 2 (DE3)
gene KDM4A, recombinant expression of His-tagged KDM4A residues 1-359 in Escherichia coli strain BL21 Codon-Plus-Ril from plasmid pNIC28-Bsa4
gene KDM4A, recombinant expression of N-terminally His-tagged enzyme in Escherichia coli
gene KDM4A, recombinant overexpression in U2O2 cells, recombinant expression of N-terminally FLAG-tagged KDM4A or KDM4A mutant H188A in HeLa cells, recombinant expression of N-terminally His6-tagged truncated KDM4A1-359 in Escherichia coli strain BL21(DE3)
gene KDM4B, phylogenetic analysis, recombinant expression of N-terminally His-tagged KDM4B catalytic domain in Escherichia coli
gene KDM4B, recombinant isozyme expression in U2OS-TetON stable cell line that conditionally expresses the fusion protein EGFP-KDM4B
gene KDM4C, phylogenetic analysis, recombinant expression of N-terminally His-tagged KDM4C catalytic domain in Escherichia coli
gene KDM4C, recombinant isozyme expression in U2OS-TetON stable cell line that conditionally expresses the fusion protein EGFP-KDM4C, recombinant expression of EGFP-tagged full-length and truncated, and mutant enzymes versions
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
KDM4A possesses the potential to act as an oxygen sensor in the context of chromatin modifications, with possible implications for epigenetic regulation in hypoxic disease states
medicine
medicine
KDM4A is both amplified and deleted across many disparate cancer types, and KDM4A expression correlates with copy number in these samples. 46% of ovarian cancer cells display KDM4A amplification, which correlates with expression
medicine
fisetin induces DNA damage via critical transcription factor RFXAP/KDM4A-dependent histone H3K36 demethylation, thus causing inhibition of proliferation in pancreatic adenocarcinoma (PDAC). Fisetin inhibits cell proliferation and induces DNA damage and S-phase arrest in PDAC. Expression of RFXAP and other DNA-damage response genes is upregulated by fisetin. RFXAP expression is relatively low in PDAC and correlates with tumor stage and poor prognosis. Fisetin enhances the effect of chemotherapy on pancreatic cancer cells
medicine
JMJD2A displays higher expression in glioma tissues than that in normal brain tissues and lower levels of H3K9me3/H3K36me3are found in glioma tissues
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Hancock, R.L.; Masson, N.; Dunne, K.; Flashman, E.; Kawamura, A.
The activity of JmjC histone lysine demethylase KDM4A is highly sensitive to oxygen concentrations
ACS Chem. Biol.
12
1011-1019
2017
Homo sapiens (O75164)
Morera, L.; Roatsch, M.; Fuerst, M.C.; Hoffmann, I.; Senger, J.; Hau, M.; Franz, H.; Schuele, R.; Heinrich, M.R.; Jung, M.
4-biphenylalanine- and 3-phenyltyrosine-derived hydroxamic acids as inhibitors of the JumonjiC-domain-containing histone demethylase KDM4A
ChemMedChem
11
2063-2083
2016
Homo sapiens (O75164)
Kupershmit, I.; Khoury-Haddad, H.; Awwad, S.W.; Guttmann-Raviv, N.; Ayoub, N.
KDM4C (GASC1) lysine demethylase is associated with mitotic chromatin and regulates chromosome segregation during mitosis
Nucleic Acids Res.
42
6168-6182
2014
Homo sapiens (O75164), Homo sapiens (O94953), Homo sapiens (Q9H3R0)
An, J.; Xu, J.; Li, J.; Jia, S.; Li, X.; Lu, Y.; Yang, Y.; Lin, Z.; Xin, X.; Wu, M.; Zheng, Q.; Pu, H.; Gui, X.; Li, T.; Lu, D.
HistoneH3 demethylase JMJD2A promotes growth of liver cancer cells through up-regulating miR372
Oncotarget
8
49093-49109
2017
Homo sapiens (O75164)
Li, W.; Zhao, L.; Zang, W.; Liu, Z.; Chen, L.; Liu, T.; Xu, D.; Jia, J.
Histone demethylase JMJD2B is required for tumor cell proliferation and survival and is overexpressed in gastric cancer
Biochem. Biophys. Res. Commun.
416
372-378
2011
Homo sapiens (O94953)
-
Marmorstein, R.; Trievel, R.C.
Histone modifying enzymes structures, mechanisms, and specificities
Biochim. Biophys. Acta
1789
58-68
2009
Homo sapiens (O75164)
Li, Q.; Ke, Q.; Costa, M.
Alterations of histone modifications by cobalt compounds
Carcinogenesis
30
1243-1251
2009
Homo sapiens (O75164)
Whetstine, J.R.; Nottke, A.; Lan, F.; Huarte, M.; Smolikov, S.; Chen, Z.; Spooner, E.; Li, E.; Zhang, G.; Colaiacovo, M.; Shi, Y.
Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases
Cell
125
467-481
2006
Caenorhabditis elegans (Q9U297), Homo sapiens (O75164)
Black, J.C.; Manning, A.L.; Van Rechem, C.; Kim, J.; Ladd, B.; Cho, J.; Pineda, C.M.; Murphy, N.; Daniels, D.L.; Montagna, C.; Lewis, P.W.; Glass, K.; Allis, C.D.; Dyson, N.J.; Getz, G.; Whetstine, J.R.
KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors
Cell
154
541-555
2013
Homo sapiens (O75164)
Pfister, S.X.; Ahrabi, S.; Zalmas, L.P.; Sarkar, S.; Aymard, F.; Bachrati, C.Z.; Helleday, T.; Legube, G.; La Thangue, N.B.; Porter, A.C.; Humphrey, T.C.
SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability
Cell Rep.
7
2006-2018
2014
Homo sapiens (O75164)
Hillringhaus, L.; Yue, W.W.; Rose, N.R.; Ng, S.S.; Gileadi, C.; Loenarz, C.; Bello, S.H.; Bray, J.E.; Schofield, C.J.; Oppermann, U.
Structural and evolutionary basis for the dual substrate selectivity of human KDM4 histone demethylase family
J. Biol. Chem.
286
41616-41625
2011
Homo sapiens (O75164), Homo sapiens (O94953), Homo sapiens (Q9H3R0)
Duan, L.; Perez, R.E.; Lai, X.; Chen, L.; Maki, C.G.
The histone demethylase JMJD2B is critical for p53-mediated autophagy and survival in Nutlin-treated cancer cells
J. Biol. Chem.
294
9186-9197
2019
Homo sapiens
Tan, M.K.; Lim, H.J.; Harper, J.W.
SCF(FBXO22) regulates histone H3 lysine 9 and 36 methylation levels by targeting histone demethylase KDM4A for ubiquitin-mediated proteasomal degradation
Mol. Cell. Biol.
31
3687-3699
2011
Homo sapiens (O75164)
Couture, J.; Collazo, E.; Ortiz-Tello, P.A.; Brunzelle, J.S.; Trievel, R.C.
Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase
Nat. Struct. Mol. Biol.
14
689-695
2007
Homo sapiens (O75164)
Klose, R.J.; Yamane, K.; Bae, Y.; Zhang, D.; Erdjument-Bromage, H.; Tempst, P.; Wong, J.; Zhang, Y.
The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36
Nature
442
312-316
2006
Homo sapiens (O75164)
Ng, S.S.; Kavanagh, K.L.; McDonough, M.A.; Butler, D.; Pilka, E.S.; Lienard, B.M.; Bray, J.E.; Savitsky, P.; Gileadi, O.; von Delft, F.; Rose, N.R.; Offer, J.; Scheinost, J.C.; Borowski, T.; Sundstrom, M.; Schofield, C.J.; Oppermann, U.
Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity
Nature
448
87-91
2007
Homo sapiens (O75164)
Gautam, D.; Johnson, B.A.; Mac, M.; Moody, C.A.
SETD2-dependent H3K36me3 plays a critical role in epigenetic regulation of the HPV31 life cycle
PLoS Pathog.
14
e1007367
2018
Homo sapiens
Chen, Z.; Zang, J.; Kappler, J.; Hong, X.; Crawford, F.; Wang, Q.; Lan, F.; Jiang, C.; Whetstine, J.; Dai, S.; Hansen, K.; Shi, Y.; Zhang, G.
Structural basis of the recognition of a methylated histone tail by JMJD2A
Proc. Natl. Acad. Sci. USA
104
10818-10823
2007
Homo sapiens (O75164)
Li, M.; Cheng, J.; Ma, Y.; Guo, H.; Shu, H.; Huang, H.; Kuang, Y.; Yang, T.
The histone demethylase JMJD2A promotes glioma cell growth via targeting Akt-mTOR signaling
Cancer Cell Int.
20
101
2020
Homo sapiens (O75164)
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