UniProt functional annotation for P29375



	UniProt functional annotation for P29375

UniProt code: P29375.

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-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. Regulates specific gene transcription through DNA-binding on 5'-CCGCCC-3' motif (PubMed:18270511). May stimulate transcription mediated by nuclear receptors. Involved in transcriptional regulation of Hox proteins during cell differentiation (PubMed:19430464). May participate in transcriptional repression of cytokines such as CXCL12. Plays a role in the regulation of the circadian rhythm and in maintaining the normal periodicity of the circadian clock. In a histone demethylase-independent manner, acts as a coactivator of the CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER1/2 and other clock-controlled genes and increases histone acetylation at PER1/2 promoters by inhibiting the activity of HDAC1 (By similarity). Seems to act as a transcriptional corepressor for some genes such as MT1F and to favor the proliferation of cancer cells (PubMed:27427228). {ECO:0000250|UniProtKB:Q3UXZ9, ECO:0000269|PubMed:11358960, ECO:0000269|PubMed:15949438, ECO:0000269|PubMed:17320160, ECO:0000269|PubMed:17320161, ECO:0000269|PubMed:17320163, ECO:0000269|PubMed:18270511, ECO:0000269|PubMed:19430464, ECO:0000269|PubMed:27427228}.

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:0000305|PubMed:17320160, ECO:0000305|PubMed:17320161, ECO:0000305|PubMed:17320163};

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

Activity regulation: The inhibitors KDOAM-25, CPI-455 and others inhibits its demethylase activity, resulting to cell growth arrest in cancer cells. {ECO:0000269|PubMed:27214401, ECO:0000269|PubMed:27427228}.

Biophysicochemical properties: Kinetic parameters: KM=9 uM for 2-oxoglutarate {ECO:0000269|PubMed:27427228}; KM=2.9 uM for histone H3K4me3 {ECO:0000269|PubMed:27427228}; Note=Kcat are 2.1 min(-1) and 1.9 min(-1) for 2-oxoglutarate and histone H3K4me3, respectively. {ECO:0000269|PubMed:27427228};

Subunit: Interacts with SUZ12; the interaction is direct (By similarity). Interacts with the viral protein-binding domain of RB1. Interacts with ESR1, MYC, MYCN and LMO2. Interacts with HDAC1 (By similarity). Interacts with ARNTL/BMAL1 and CLOCK. Interacts (via PHD- type 1 zinc finger) with histone H3 unmodified at 'Lys-4' and (via PHD- type 3 zinc finger) with histone H3 di- and trimethylated at 'Lys-4' (PubMed:19430464). {ECO:0000250|UniProtKB:Q3UXZ9, ECO:0000269|PubMed:11358960, ECO:0000269|PubMed:15949438, ECO:0000269|PubMed:17311883, ECO:0000269|PubMed:19430464, ECO:0000269|PubMed:21960634, ECO:0000269|PubMed:7935440, ECO:0000269|PubMed:8414517, ECO:0000269|PubMed:9129143}.

Subcellular location: Nucleus, nucleolus {ECO:0000269|PubMed:15949438, ECO:0000269|PubMed:7935440}. Nucleus {ECO:0000250|UniProtKB:Q3UXZ9}. Note=Occupies promoters of genes involved in RNA metabolism and mitochondrial function. {ECO:0000250|UniProtKB:Q3UXZ9}.

Domain: The GSGFP motif is required for the interaction with SUZ12 (By similarity). The ARID domain specifically binds to the CCGCCC motif and is required for the lysine-specific histone demethylase activity (PubMed:18270511). The PHD-type 3 zinc finger is required for the interaction with histone H3 di- and trimethylated at 'Lys-4' (PubMed:19430464). {ECO:0000250|UniProtKB:Q3UXZ9, ECO:0000269|PubMed:18270511, ECO:0000269|PubMed:19430464}.

Disease: Note=A chromosomal aberration involving KDM5A has been found in M5 type acute myeloid leukemia. Translocation t(11;12)(p15;p13) with NUP98. {ECO:0000269|PubMed:23531517}.

Disease: Note=Chromosomal aberrations involving KDM5A have been found in M7 type childhood acute myeloid leukemia. Translocation t(11;12)(p15;p13) with NUP98. {ECO:0000269|PubMed:16419055, ECO:0000269|PubMed:23531517}.

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

Sequence caution: Sequence=AAB28544.1; Type=Frameshift; Evidence={ECO:0000305}; Sequence=BAE06081.1; 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 specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. Regulates specific gene transcription through DNA-binding on 5'-CCGCCC-3' motif (PubMed:18270511). May stimulate transcription mediated by nuclear receptors. Involved in transcriptional regulation of Hox proteins during cell differentiation (PubMed:19430464). May participate in transcriptional repression of cytokines such as CXCL12. Plays a role in the regulation of the circadian rhythm and in maintaining the normal periodicity of the circadian clock. In a histone demethylase-independent manner, acts as a coactivator of the CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER1/2 and other clock-controlled genes and increases histone acetylation at PER1/2 promoters by inhibiting the activity of HDAC1 (By similarity). Seems to act as a transcriptional corepressor for some genes such as MT1F and to favor the proliferation of cancer cells (PubMed:27427228). {ECO:0000250\|UniProtKB:Q3UXZ9, ECO:0000269\|PubMed:11358960, ECO:0000269\|PubMed:15949438, ECO:0000269\|PubMed:17320160, ECO:0000269\|PubMed:17320161, ECO:0000269\|PubMed:17320163, ECO:0000269\|PubMed:18270511, ECO:0000269\|PubMed:19430464, ECO:0000269\|PubMed:27427228}.


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:0000305\|PubMed:17320160, ECO:0000305\|PubMed:17320161, ECO:0000305\|PubMed:17320163};
Cofactor:		Name=Fe(2+); Xref=ChEBI:CHEBI:29033; Evidence={ECO:0000250}; Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000250};
Activity regulation:		The inhibitors KDOAM-25, CPI-455 and others inhibits its demethylase activity, resulting to cell growth arrest in cancer cells. {ECO:0000269\|PubMed:27214401, ECO:0000269\|PubMed:27427228}.
Biophysicochemical properties:		Kinetic parameters: KM=9 uM for 2-oxoglutarate {ECO:0000269\|PubMed:27427228}; KM=2.9 uM for histone H3K4me3 {ECO:0000269\|PubMed:27427228}; Note=Kcat are 2.1 min(-1) and 1.9 min(-1) for 2-oxoglutarate and histone H3K4me3, respectively. {ECO:0000269\|PubMed:27427228};
Subunit:		Interacts with SUZ12; the interaction is direct (By similarity). Interacts with the viral protein-binding domain of RB1. Interacts with ESR1, MYC, MYCN and LMO2. Interacts with HDAC1 (By similarity). Interacts with ARNTL/BMAL1 and CLOCK. Interacts (via PHD- type 1 zinc finger) with histone H3 unmodified at 'Lys-4' and (via PHD- type 3 zinc finger) with histone H3 di- and trimethylated at 'Lys-4' (PubMed:19430464). {ECO:0000250\|UniProtKB:Q3UXZ9, ECO:0000269\|PubMed:11358960, ECO:0000269\|PubMed:15949438, ECO:0000269\|PubMed:17311883, ECO:0000269\|PubMed:19430464, ECO:0000269\|PubMed:21960634, ECO:0000269\|PubMed:7935440, ECO:0000269\|PubMed:8414517, ECO:0000269\|PubMed:9129143}.
Subcellular location:		Nucleus, nucleolus {ECO:0000269\|PubMed:15949438, ECO:0000269\|PubMed:7935440}. Nucleus {ECO:0000250\|UniProtKB:Q3UXZ9}. Note=Occupies promoters of genes involved in RNA metabolism and mitochondrial function. {ECO:0000250\|UniProtKB:Q3UXZ9}.
Domain:		The GSGFP motif is required for the interaction with SUZ12 (By similarity). The ARID domain specifically binds to the CCGCCC motif and is required for the lysine-specific histone demethylase activity (PubMed:18270511). The PHD-type 3 zinc finger is required for the interaction with histone H3 di- and trimethylated at 'Lys-4' (PubMed:19430464). {ECO:0000250\|UniProtKB:Q3UXZ9, ECO:0000269\|PubMed:18270511, ECO:0000269\|PubMed:19430464}.
Disease:		Note=A chromosomal aberration involving KDM5A has been found in M5 type acute myeloid leukemia. Translocation t(11;12)(p15;p13) with NUP98. {ECO:0000269\|PubMed:23531517}.
Disease:		Note=Chromosomal aberrations involving KDM5A have been found in M7 type childhood acute myeloid leukemia. Translocation t(11;12)(p15;p13) with NUP98. {ECO:0000269\|PubMed:16419055, ECO:0000269\|PubMed:23531517}.
Similarity:		Belongs to the JARID1 histone demethylase family. {ECO:0000305}.
Sequence caution:		Sequence=AAB28544.1; Type=Frameshift; Evidence={ECO:0000305}; Sequence=BAE06081.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};