UniProt functional annotation for O75164



	UniProt functional annotation for O75164

UniProt code: O75164.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code (PubMed:26741168). Does not demethylate histone H3 'Lys- 4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively. {ECO:0000269|PubMed:16024779, ECO:0000269|PubMed:16603238, ECO:0000269|PubMed:26741168}.

Function: [Isoform 2]: Crucial for muscle differentiation, promotes transcriptional activation of the Myog gene by directing the removal of repressive chromatin marks at its promoter. Lacks the N-terminal demethylase domain. {ECO:0000269|PubMed:21694756}.

Catalytic activity: Reaction=2 2-oxoglutarate + N(6),N(6),N(6)-trimethyl-L-lysyl(9)- [histone H3] + 2 O2 = 2 CO2 + 2 formaldehyde + N(6)-methyl-L- lysyl(9)-[histone H3] + 2 succinate; Xref=Rhea:RHEA:60200, Rhea:RHEA- COMP:15538, Rhea:RHEA-COMP:15542, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:61929, ChEBI:CHEBI:61961; EC=1.14.11.66; Evidence={ECO:0000269|PubMed:16603238};

Catalytic activity: Reaction=2 2-oxoglutarate + N(6),N(6),N(6)-trimethyl-L-lysyl(36)- [histone H3] + 2 O2 = 2 CO2 + 2 formaldehyde + N(6)-methyl-L- lysyl(36)-[histone H3] + 2 succinate; Xref=Rhea:RHEA:60236, Rhea:RHEA-COMP:9786, Rhea:RHEA-COMP:15536, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:61929, ChEBI:CHEBI:61961; EC=1.14.11.69; Evidence={ECO:0000269|PubMed:16603238};

Cofactor: Name=Fe(2+); Xref=ChEBI:CHEBI:29033; Evidence={ECO:0000269|PubMed:16603238}; Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000269|PubMed:16603238};

Activity regulation: Several specific inhibitors are being developed and tested. {ECO:0000269|PubMed:26741168}.

Subunit: Interacts with histone deacetylase proteins HDAC1, HDAC2 and HDAC3. Interacts with RB and NCOR1. {ECO:0000269|PubMed:15927959, ECO:0000269|PubMed:16024779, ECO:0000269|PubMed:16601153, ECO:0000269|PubMed:16677698}.

Subunit: (Microbial infection) Interacts with HTLV-1 Tax protein. {ECO:0000269|PubMed:15927959}.

Subcellular location: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00537, ECO:0000269|PubMed:15927959, ECO:0000269|PubMed:16024779}.

Tissue specificity: Ubiquitous. {ECO:0000269|PubMed:15927959}.

Domain: The 2 Tudor domains recognize and bind methylated histone H3 'Lys-4' residue (H3K4me). Double Tudor domain has an interdigitated structure and the unusual fold is required for its ability to bind methylated histone tails. Trimethylated H3 'Lys-4' (H3K4me3) is bound in a cage of 3 aromatic residues, 2 of which are from the Tudor domain 2, while the binding specificity is determined by side-chain interactions involving residues from the Tudor domain 1. The Tudor domains are also able to bind trimethylated histone H3 'Lys-9' (H3K9me3), di- and trimethylated H4 'Lys-20' (H4K20me2 and H4K20me3). Has high affinity for H4K20me2, blocking recruitment of proteins such as TP53BP1. {ECO:0000269|PubMed:16415788, ECO:0000269|PubMed:16601153, ECO:0000269|PubMed:16603238, ECO:0000269|PubMed:22373579}.

Ptm: Ubiquitinated by RNF8 and RNF168 following DNA damage, leading to its degradation. Degradation promotes accessibility of H4K20me2 mark for DNA repair protein TP53BP1, which is then recruited. {ECO:0000269|PubMed:22373579}.

Similarity: Belongs to the JHDM3 histone demethylase family. {ECO:0000305}.

Sequence caution: Sequence=BAA31652.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code (PubMed:26741168). Does not demethylate histone H3 'Lys- 4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate. Participates in transcriptional repression of ASCL2 and E2F-responsive promoters via the recruitment of histone deacetylases and NCOR1, respectively. {ECO:0000269\|PubMed:16024779, ECO:0000269\|PubMed:16603238, ECO:0000269\|PubMed:26741168}.



Function:		[Isoform 2]: Crucial for muscle differentiation, promotes transcriptional activation of the Myog gene by directing the removal of repressive chromatin marks at its promoter. Lacks the N-terminal demethylase domain. {ECO:0000269\|PubMed:21694756}.


Catalytic activity:		Reaction=2 2-oxoglutarate + N(6),N(6),N(6)-trimethyl-L-lysyl(9)- [histone H3] + 2 O2 = 2 CO2 + 2 formaldehyde + N(6)-methyl-L- lysyl(9)-[histone H3] + 2 succinate; Xref=Rhea:RHEA:60200, Rhea:RHEA- COMP:15538, Rhea:RHEA-COMP:15542, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:61929, ChEBI:CHEBI:61961; EC=1.14.11.66; Evidence={ECO:0000269\|PubMed:16603238};
Catalytic activity:		Reaction=2 2-oxoglutarate + N(6),N(6),N(6)-trimethyl-L-lysyl(36)- [histone H3] + 2 O2 = 2 CO2 + 2 formaldehyde + N(6)-methyl-L- lysyl(36)-[histone H3] + 2 succinate; Xref=Rhea:RHEA:60236, Rhea:RHEA-COMP:9786, Rhea:RHEA-COMP:15536, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:30031, ChEBI:CHEBI:61929, ChEBI:CHEBI:61961; EC=1.14.11.69; Evidence={ECO:0000269\|PubMed:16603238};
Cofactor:		Name=Fe(2+); Xref=ChEBI:CHEBI:29033; Evidence={ECO:0000269\|PubMed:16603238}; Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000269\|PubMed:16603238};
Activity regulation:		Several specific inhibitors are being developed and tested. {ECO:0000269\|PubMed:26741168}.
Subunit:		Interacts with histone deacetylase proteins HDAC1, HDAC2 and HDAC3. Interacts with RB and NCOR1. {ECO:0000269\|PubMed:15927959, ECO:0000269\|PubMed:16024779, ECO:0000269\|PubMed:16601153, ECO:0000269\|PubMed:16677698}.
Subunit:		(Microbial infection) Interacts with HTLV-1 Tax protein. {ECO:0000269\|PubMed:15927959}.
Subcellular location:		Nucleus {ECO:0000255\|PROSITE-ProRule:PRU00537, ECO:0000269\|PubMed:15927959, ECO:0000269\|PubMed:16024779}.
Tissue specificity:		Ubiquitous. {ECO:0000269\|PubMed:15927959}.
Domain:		The 2 Tudor domains recognize and bind methylated histone H3 'Lys-4' residue (H3K4me). Double Tudor domain has an interdigitated structure and the unusual fold is required for its ability to bind methylated histone tails. Trimethylated H3 'Lys-4' (H3K4me3) is bound in a cage of 3 aromatic residues, 2 of which are from the Tudor domain 2, while the binding specificity is determined by side-chain interactions involving residues from the Tudor domain 1. The Tudor domains are also able to bind trimethylated histone H3 'Lys-9' (H3K9me3), di- and trimethylated H4 'Lys-20' (H4K20me2 and H4K20me3). Has high affinity for H4K20me2, blocking recruitment of proteins such as TP53BP1. {ECO:0000269\|PubMed:16415788, ECO:0000269\|PubMed:16601153, ECO:0000269\|PubMed:16603238, ECO:0000269\|PubMed:22373579}.
Ptm:		Ubiquitinated by RNF8 and RNF168 following DNA damage, leading to its degradation. Degradation promotes accessibility of H4K20me2 mark for DNA repair protein TP53BP1, which is then recruited. {ECO:0000269\|PubMed:22373579}.
Similarity:		Belongs to the JHDM3 histone demethylase family. {ECO:0000305}.
Sequence caution:		Sequence=BAA31652.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};