UniProt functional annotation for Q8N371



	UniProt functional annotation for Q8N371

UniProt code: Q8N371.

Organism: Homo sapiens (Human).

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

Function: Bifunctional enzyme that acts both as an endopeptidase and 2- oxoglutarate-dependent monoxygenase (PubMed:28847961, PubMed:29459673, PubMed:28982940, PubMed:29563586). Endopeptidase that cleaves histones N-terminal tails at the carboxyl side of methylated arginine or lysine residues, to generate 'tailless nucleosomes', which may trigger transcription elongation (PubMed:28847961, PubMed:29459673, PubMed:28982940). Preferentially recognizes and cleaves monomethylated and dimethylated arginine residues of histones H2, H3 and H4. After initial cleavage, continues to digest histones tails via its aminopeptidase activity (PubMed:28847961, PubMed:29459673). Upon DNA damage, cleaves the N-terminal tail of histone H3 at monomethylated lysine residues, preferably at monomethylated 'Lys-9' (H3K9me1). The histone variant H3F3A is the major target for cleavage (PubMed:28982940). Additionnally, acts as Fe(2+) and 2-oxoglutarate- dependent monoxygenase, catalyzing (R)-stereospecific hydroxylation at C-3 of 'Arg-137' of RPS6 and 'Arg-141' of RCCD1, but the biological significance of this activity remains to be established (PubMed:29563586). Regulates mitosis through different mechanisms: Plays a role in transcriptional repression of satellite repeats, possibly by regulating H3K36 methylation levels in centromeric regions together with RCCD1. Possibly together with RCCD1, is involved in proper mitotic spindle organization and chromosome segregation (PubMed:24981860). Negatively regulates cell cycle repressor CDKN1A/p21, which controls G1/S phase transition (PubMed:24740926). Required for G2/M phase cell cycle progression. Regulates expression of CCNA1/cyclin-A1, leading to cancer cell proliferation (PubMed:20457893). Also, plays a role in regulating alpha-tubulin acetylation and cytoskeletal microtubule stability involved in epithelial to mesenchymal transition (PubMed:28455245). Regulates the circadian gene expression in the liver (By similarity). Represses the transcriptional activator activity of the CLOCK-ARNTL/BMAL1 heterodimer in a catalytically-independent manner (PubMed:30500822). Negatively regulates the protein stability and function of CRY1; required for AMPK-FBXL3-induced CRY1 degradation (PubMed:30500822). {ECO:0000250|UniProtKB:Q9CXT6, ECO:0000269|PubMed:20457893, ECO:0000269|PubMed:24740926, ECO:0000269|PubMed:24981860, ECO:0000269|PubMed:28455245, ECO:0000269|PubMed:28847961, ECO:0000269|PubMed:28982940, ECO:0000269|PubMed:29459673, ECO:0000269|PubMed:29563586, ECO:0000269|PubMed:30500822}.

Catalytic activity: Reaction=2-oxoglutarate + L-arginyl-[protein] + O2 = (3R)-3-hydroxy-L- arginyl-[protein] + CO2 + succinate; Xref=Rhea:RHEA:56744, Rhea:RHEA- COMP:10532, Rhea:RHEA-COMP:14712, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:29965, ChEBI:CHEBI:30031, ChEBI:CHEBI:78294; EC=1.14.11.73; Evidence={ECO:0000269|PubMed:29563586};

Cofactor: Name=Fe(2+); Xref=ChEBI:CHEBI:29033; Evidence={ECO:0000269|PubMed:24981860, ECO:0000269|PubMed:28982940, ECO:0000269|PubMed:29563586}; Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000305|PubMed:24100311};

Biophysicochemical properties: Kinetic parameters: KM=60.4 uM for ARG-137 of RPS6 {ECO:0000269|PubMed:29563586}; Note=KM>300 uM for ARG-141 of RCCD1. {ECO:0000269|PubMed:29563586};

Subunit: Can form homodimers (via JmjC domain) (PubMed:24100311, PubMed:28982940). Found in a complex with RCCD1 (PubMed:24981860). Interacts (via N-terminus) with RCCD1 (via N-terminus); this interaction stimulates H3K36me3 and H3K36me2 demethylation (PubMed:28455245, PubMed:24981860). Interacts (via JmjC domain) with H3C1 (PubMed:28982940). Interacts with FBXL3 and PSMD2 (By similarity). Interacts with CRY1 in a FBXL3-dependent manner (By similarity). {ECO:0000250|UniProtKB:Q9CXT6, ECO:0000269|PubMed:24100311, ECO:0000269|PubMed:24981860, ECO:0000269|PubMed:28455245, ECO:0000269|PubMed:28982940}.

Subcellular location: Nucleus {ECO:0000269|PubMed:20457893, ECO:0000269|PubMed:28982940}. Chromosome {ECO:0000269|PubMed:24981860}. Note=Colocalizes with trimethylated 'Lys-9' of histone H3 (H3K9me3). {ECO:0000269|PubMed:24981860}.

Tissue specificity: Weakly expressed in most cells. Highly expressed in breast cancer cells (PubMed:20457893). Expressed in embryonic stem cells (PubMed:24740926). {ECO:0000269|PubMed:20457893, ECO:0000269|PubMed:24740926}.

Induction: Up-regulated upon starvation, DNA replication stress, UV treatment and by camptothecin and etoposide treatment. {ECO:0000269|PubMed:28982940}.

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:		Bifunctional enzyme that acts both as an endopeptidase and 2- oxoglutarate-dependent monoxygenase (PubMed:28847961, PubMed:29459673, PubMed:28982940, PubMed:29563586). Endopeptidase that cleaves histones N-terminal tails at the carboxyl side of methylated arginine or lysine residues, to generate 'tailless nucleosomes', which may trigger transcription elongation (PubMed:28847961, PubMed:29459673, PubMed:28982940). Preferentially recognizes and cleaves monomethylated and dimethylated arginine residues of histones H2, H3 and H4. After initial cleavage, continues to digest histones tails via its aminopeptidase activity (PubMed:28847961, PubMed:29459673). Upon DNA damage, cleaves the N-terminal tail of histone H3 at monomethylated lysine residues, preferably at monomethylated 'Lys-9' (H3K9me1). The histone variant H3F3A is the major target for cleavage (PubMed:28982940). Additionnally, acts as Fe(2+) and 2-oxoglutarate- dependent monoxygenase, catalyzing (R)-stereospecific hydroxylation at C-3 of 'Arg-137' of RPS6 and 'Arg-141' of RCCD1, but the biological significance of this activity remains to be established (PubMed:29563586). Regulates mitosis through different mechanisms: Plays a role in transcriptional repression of satellite repeats, possibly by regulating H3K36 methylation levels in centromeric regions together with RCCD1. Possibly together with RCCD1, is involved in proper mitotic spindle organization and chromosome segregation (PubMed:24981860). Negatively regulates cell cycle repressor CDKN1A/p21, which controls G1/S phase transition (PubMed:24740926). Required for G2/M phase cell cycle progression. Regulates expression of CCNA1/cyclin-A1, leading to cancer cell proliferation (PubMed:20457893). Also, plays a role in regulating alpha-tubulin acetylation and cytoskeletal microtubule stability involved in epithelial to mesenchymal transition (PubMed:28455245). Regulates the circadian gene expression in the liver (By similarity). Represses the transcriptional activator activity of the CLOCK-ARNTL/BMAL1 heterodimer in a catalytically-independent manner (PubMed:30500822). Negatively regulates the protein stability and function of CRY1; required for AMPK-FBXL3-induced CRY1 degradation (PubMed:30500822). {ECO:0000250\|UniProtKB:Q9CXT6, ECO:0000269\|PubMed:20457893, ECO:0000269\|PubMed:24740926, ECO:0000269\|PubMed:24981860, ECO:0000269\|PubMed:28455245, ECO:0000269\|PubMed:28847961, ECO:0000269\|PubMed:28982940, ECO:0000269\|PubMed:29459673, ECO:0000269\|PubMed:29563586, ECO:0000269\|PubMed:30500822}.


Catalytic activity:		Reaction=2-oxoglutarate + L-arginyl-[protein] + O2 = (3R)-3-hydroxy-L- arginyl-[protein] + CO2 + succinate; Xref=Rhea:RHEA:56744, Rhea:RHEA- COMP:10532, Rhea:RHEA-COMP:14712, ChEBI:CHEBI:15379, ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:29965, ChEBI:CHEBI:30031, ChEBI:CHEBI:78294; EC=1.14.11.73; Evidence={ECO:0000269\|PubMed:29563586};
Cofactor:		Name=Fe(2+); Xref=ChEBI:CHEBI:29033; Evidence={ECO:0000269\|PubMed:24981860, ECO:0000269\|PubMed:28982940, ECO:0000269\|PubMed:29563586}; Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000305\|PubMed:24100311};
Biophysicochemical properties:		Kinetic parameters: KM=60.4 uM for ARG-137 of RPS6 {ECO:0000269\|PubMed:29563586}; Note=KM>300 uM for ARG-141 of RCCD1. {ECO:0000269\|PubMed:29563586};
Subunit:		Can form homodimers (via JmjC domain) (PubMed:24100311, PubMed:28982940). Found in a complex with RCCD1 (PubMed:24981860). Interacts (via N-terminus) with RCCD1 (via N-terminus); this interaction stimulates H3K36me3 and H3K36me2 demethylation (PubMed:28455245, PubMed:24981860). Interacts (via JmjC domain) with H3C1 (PubMed:28982940). Interacts with FBXL3 and PSMD2 (By similarity). Interacts with CRY1 in a FBXL3-dependent manner (By similarity). {ECO:0000250\|UniProtKB:Q9CXT6, ECO:0000269\|PubMed:24100311, ECO:0000269\|PubMed:24981860, ECO:0000269\|PubMed:28455245, ECO:0000269\|PubMed:28982940}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:20457893, ECO:0000269\|PubMed:28982940}. Chromosome {ECO:0000269\|PubMed:24981860}. Note=Colocalizes with trimethylated 'Lys-9' of histone H3 (H3K9me3). {ECO:0000269\|PubMed:24981860}.
Tissue specificity:		Weakly expressed in most cells. Highly expressed in breast cancer cells (PubMed:20457893). Expressed in embryonic stem cells (PubMed:24740926). {ECO:0000269\|PubMed:20457893, ECO:0000269\|PubMed:24740926}.
Induction:		Up-regulated upon starvation, DNA replication stress, UV treatment and by camptothecin and etoposide treatment. {ECO:0000269\|PubMed:28982940}.