UniProt functional annotation for Q9UGL1



	UniProt functional annotation for Q9UGL1

UniProt code: Q9UGL1.

Organism: Homo sapiens (Human).

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

Function: Histone demethylase that demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code (PubMed:24952722, PubMed:27214403, PubMed:28262558). Does not demethylate histone H3 'Lys-9' or H3 'Lys-27'. Demethylates trimethylated, dimethylated and monomethylated H3 'Lys-4'. Acts as a transcriptional corepressor for FOXG1B and PAX9. Favors the proliferation of breast cancer cells by repressing tumor suppressor genes such as BRCA1 and HOXA5 (PubMed:24952722). In contrast, may act as a tumor suppressor for melanoma. Represses the CLOCK-ARNTL/BMAL1 heterodimer-mediated transcriptional activation of the core clock component PER2 (By similarity). {ECO:0000250|UniProtKB:Q80Y84, ECO:0000269|PubMed:12657635, ECO:0000269|PubMed:16645588, ECO:0000269|PubMed:17320161, ECO:0000269|PubMed:17363312, ECO:0000269|PubMed:24952722, ECO:0000269|PubMed:26645689, ECO:0000269|PubMed:26741168, ECO:0000269|PubMed:27214403, ECO:0000269|PubMed:28262558}.

Catalytic activity: Reaction=3 2-oxoglutarate + N(6),N(6),N(6)-trimethyl-L-lysyl(4)- [histone H3] + 3 O2 = 3 CO2 + 3 formaldehyde + L-lysyl(4)-[histone H3] + 3 succinate; Xref=Rhea:RHEA:60208, Rhea:RHEA-COMP:15537, Rhea:RHEA-COMP:15547, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:29969, ChEBI:CHEBI:30031, ChEBI:CHEBI:61961; EC=1.14.11.67; Evidence={ECO:0000250|UniProtKB:Q80Y84};

Cofactor: Name=Fe(2+); Xref=ChEBI:CHEBI:29033; Evidence={ECO:0000250}; Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000250};

Activity regulation: Several specific inhibitors are being developed and tested (PubMed:27214403, PubMed:26741168). The inhibitor KDOAM-25 inhibits its demethylase activity, resulting to cell cycle arrest in myeloma cells (PubMed:28262558). {ECO:0000269|PubMed:26741168, ECO:0000269|PubMed:27214403, ECO:0000269|PubMed:28262558}.

Biophysicochemical properties: Kinetic parameters: KM=9 uM for 2-oxoglutarate {ECO:0000269|PubMed:26645689}; KM=4 uM for histone H3K4me3 {ECO:0000269|PubMed:26645689}; Note=Kcat are 1.9 min(-1) and 2.0 min(-1) for 2-oxoglutarate and histone H3K4me3, respectively. {ECO:0000269|PubMed:26645689};

Subunit: Interacts with FOXG1B, PAX9, MYC, MYCN and RB1. Interacts with HDAC1, HDAC4, HDAC5 and HDAC7. Interacts (via PHD-type 1 zinc finger) with histone H3 unmodified at 'Lys-4'; the interaction is inhibited when histone H3 is methylated at 'Arg-2' or 'Lys-4' (PubMed:24952722). {ECO:0000269|PubMed:12657635, ECO:0000269|PubMed:15803180, ECO:0000269|PubMed:16645588, ECO:0000269|PubMed:17311883, ECO:0000269|PubMed:17373667, ECO:0000269|PubMed:24952722}.

Subcellular location: Nucleus {ECO:0000255|PROSITE-ProRule:PRU00355, ECO:0000255|PROSITE-ProRule:PRU00537, ECO:0000269|PubMed:10336460, ECO:0000269|PubMed:12237901}.

Tissue specificity: Ubiquitously expressed, with highest levels in testis. Down-regulated in melanoma and glioblastoma. Up-regulated in breast cancer (at protein level). {ECO:0000269|PubMed:10336460, ECO:0000269|PubMed:10616211, ECO:0000269|PubMed:10878660, ECO:0000269|PubMed:12237901, ECO:0000269|PubMed:15803180}.

Domain: Both the JmjC domain and the JmjN domain are required for enzymatic activity. However ARID and PHD-type 1 domain are not required for activity per se but contributed to recognition of the H3(1-21)K4me2 substrate peptide. {ECO:0000269|PubMed:27214403}.

Domain: The 2 first PHD-type zinc finger domains are required for transcription repression activity.

Disease: Mental retardation, autosomal recessive 65 (MRT65) [MIM:618109]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT65 patients have moderate to severe intellectual disability, developmental delay, and facial dysmorphism. Camptodactyly is present in some patients. {ECO:0000269|PubMed:29276005, ECO:0000269|PubMed:30409806}. Note=The disease may be caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the JARID1 histone demethylase family. {ECO:0000305}.

Sequence caution: Sequence=CAB63108.1; 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 demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code (PubMed:24952722, PubMed:27214403, PubMed:28262558). Does not demethylate histone H3 'Lys-9' or H3 'Lys-27'. Demethylates trimethylated, dimethylated and monomethylated H3 'Lys-4'. Acts as a transcriptional corepressor for FOXG1B and PAX9. Favors the proliferation of breast cancer cells by repressing tumor suppressor genes such as BRCA1 and HOXA5 (PubMed:24952722). In contrast, may act as a tumor suppressor for melanoma. Represses the CLOCK-ARNTL/BMAL1 heterodimer-mediated transcriptional activation of the core clock component PER2 (By similarity). {ECO:0000250\|UniProtKB:Q80Y84, ECO:0000269\|PubMed:12657635, ECO:0000269\|PubMed:16645588, ECO:0000269\|PubMed:17320161, ECO:0000269\|PubMed:17363312, ECO:0000269\|PubMed:24952722, ECO:0000269\|PubMed:26645689, ECO:0000269\|PubMed:26741168, ECO:0000269\|PubMed:27214403, ECO:0000269\|PubMed:28262558}.


Catalytic activity:		Reaction=3 2-oxoglutarate + N(6),N(6),N(6)-trimethyl-L-lysyl(4)- [histone H3] + 3 O2 = 3 CO2 + 3 formaldehyde + L-lysyl(4)-[histone H3] + 3 succinate; Xref=Rhea:RHEA:60208, Rhea:RHEA-COMP:15537, Rhea:RHEA-COMP:15547, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842, ChEBI:CHEBI:29969, ChEBI:CHEBI:30031, ChEBI:CHEBI:61961; EC=1.14.11.67; Evidence={ECO:0000250\|UniProtKB:Q80Y84};
Cofactor:		Name=Fe(2+); Xref=ChEBI:CHEBI:29033; Evidence={ECO:0000250}; Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000250};
Activity regulation:		Several specific inhibitors are being developed and tested (PubMed:27214403, PubMed:26741168). The inhibitor KDOAM-25 inhibits its demethylase activity, resulting to cell cycle arrest in myeloma cells (PubMed:28262558). {ECO:0000269\|PubMed:26741168, ECO:0000269\|PubMed:27214403, ECO:0000269\|PubMed:28262558}.
Biophysicochemical properties:		Kinetic parameters: KM=9 uM for 2-oxoglutarate {ECO:0000269\|PubMed:26645689}; KM=4 uM for histone H3K4me3 {ECO:0000269\|PubMed:26645689}; Note=Kcat are 1.9 min(-1) and 2.0 min(-1) for 2-oxoglutarate and histone H3K4me3, respectively. {ECO:0000269\|PubMed:26645689};
Subunit:		Interacts with FOXG1B, PAX9, MYC, MYCN and RB1. Interacts with HDAC1, HDAC4, HDAC5 and HDAC7. Interacts (via PHD-type 1 zinc finger) with histone H3 unmodified at 'Lys-4'; the interaction is inhibited when histone H3 is methylated at 'Arg-2' or 'Lys-4' (PubMed:24952722). {ECO:0000269\|PubMed:12657635, ECO:0000269\|PubMed:15803180, ECO:0000269\|PubMed:16645588, ECO:0000269\|PubMed:17311883, ECO:0000269\|PubMed:17373667, ECO:0000269\|PubMed:24952722}.
Subcellular location:		Nucleus {ECO:0000255\|PROSITE-ProRule:PRU00355, ECO:0000255\|PROSITE-ProRule:PRU00537, ECO:0000269\|PubMed:10336460, ECO:0000269\|PubMed:12237901}.
Tissue specificity:		Ubiquitously expressed, with highest levels in testis. Down-regulated in melanoma and glioblastoma. Up-regulated in breast cancer (at protein level). {ECO:0000269\|PubMed:10336460, ECO:0000269\|PubMed:10616211, ECO:0000269\|PubMed:10878660, ECO:0000269\|PubMed:12237901, ECO:0000269\|PubMed:15803180}.
Domain:		Both the JmjC domain and the JmjN domain are required for enzymatic activity. However ARID and PHD-type 1 domain are not required for activity per se but contributed to recognition of the H3(1-21)K4me2 substrate peptide. {ECO:0000269\|PubMed:27214403}.
Domain:		The 2 first PHD-type zinc finger domains are required for transcription repression activity.
Disease:		Mental retardation, autosomal recessive 65 (MRT65) [MIM:618109]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT65 patients have moderate to severe intellectual disability, developmental delay, and facial dysmorphism. Camptodactyly is present in some patients. {ECO:0000269\|PubMed:29276005, ECO:0000269\|PubMed:30409806}. Note=The disease may be caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the JARID1 histone demethylase family. {ECO:0000305}.
Sequence caution:		Sequence=CAB63108.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};