UniProt functional annotation for P54132



	UniProt functional annotation for P54132

UniProt code: P54132.

Organism: Homo sapiens (Human).

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

Function: ATP-dependent DNA helicase that unwinds single- and double- stranded DNA in a 3'-5' direction (PubMed:9388193, PubMed:24816114, PubMed:25901030). Participates in DNA replication and repair (PubMed:12019152, PubMed:21325134, PubMed:23509288). Involved in 5'-end resection of DNA during double-strand break (DSB) repair: unwinds DNA and recruits DNA2 which mediates the cleavage of 5'-ssDNA (PubMed:21325134). Negatively regulates sister chromatid exchange (SCE) (PubMed:25901030). Stimulates DNA 4-way junction branch migration and DNA Holliday junction dissolution (PubMed:25901030). Binds single- stranded DNA (ssDNA), forked duplex DNA and DNA Holliday junction (PubMed:20639533, PubMed:24257077, PubMed:25901030). Recruited by the KHDC3L-OOEP scaffold to DNA replication forks where it is retained by TRIM25 ubiquitination, it thereby promotes the restart of stalled replication forks (By similarity). {ECO:0000250|UniProtKB:O88700, ECO:0000269|PubMed:12019152, ECO:0000269|PubMed:20639533, ECO:0000269|PubMed:21325134, ECO:0000269|PubMed:23509288, ECO:0000269|PubMed:24257077, ECO:0000269|PubMed:24816114, ECO:0000269|PubMed:25901030, ECO:0000269|PubMed:9388193}.

Catalytic activity: Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.12; Evidence={ECO:0000269|PubMed:24816114, ECO:0000269|PubMed:25901030};

Cofactor: Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269|PubMed:24816114, ECO:0000269|PubMed:25901030}; Note=Binds 1 zinc ion per subunit. {ECO:0000269|PubMed:24816114, ECO:0000269|PubMed:25901030};

Subunit: Monomer (PubMed:28228481). Homodimer (via N-terminus) (PubMed:28228481). Homotetramer (via N-terminus); dimer of dimers (PubMed:28228481). Homohexamer (via N-terminus) (PubMed:28228481). Self-association negatively regulates DNA unwinding amplitude and rate. Oligomeric complexes dissociate into monomer in presence of ATP (PubMed:28228481). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with RMI complex. Interacts directly with RMI1 (via N-terminal region) component of RMI complex. Found in a complex, at least composed of BLM, RAD51 and SPIDR; the complex formation is mediated by SPIDR. Interacts with the KHDC3L/FILIA- OOEP/FLOPED scaffold complex and TRIM25 at DNA replication forks (By similarity). Interacts with ubiquitinated FANCD2 (PubMed:15257300). Interacts with SUPV3L1 (PubMed:17961633). Interacts with TOP3A (via N- terminal region). Interacts with SPIDR (via C-terminal region); the interaction is direct and required to target BLM to sites of DNA damage. {ECO:0000250|UniProtKB:O88700, ECO:0000269|PubMed:15257300, ECO:0000269|PubMed:15775963, ECO:0000269|PubMed:16595695, ECO:0000269|PubMed:17961633, ECO:0000269|PubMed:18923082, ECO:0000269|PubMed:18923083, ECO:0000269|PubMed:21325134, ECO:0000269|PubMed:23509288, ECO:0000269|PubMed:28228481}.

Subcellular location: Nucleus {ECO:0000269|PubMed:23509288}. Note=Together with SPIDR, is redistributed in discrete nuclear DNA damage-induced foci following hydroxyurea (HU) or camptothecin (CPT) treatment. Accumulated at sites of DNA damage in a RMI complex- and SPIDR-dependent manner.

Domain: The N-terminal region mediates dimerization and homooligomerization (PubMed:28228481). Both the helicase ATP-binding domain and the helicase C-terminal domain form intramolecular interactions with the HRDC domain in a ATP-dependent manner (PubMed:25901030). The HRDC domain is required for single-stranded DNA (ssDNA) and DNA Holliday junction binding (PubMed:20639533). {ECO:0000269|PubMed:20639533, ECO:0000269|PubMed:25901030, ECO:0000269|PubMed:28228481}.

Ptm: Poly-ubiquitinated by TRIM25 at Lys-259. {ECO:0000250|UniProtKB:O88700}.

Ptm: Phosphorylated in response to DNA damage. Phosphorylation requires the FANCA-FANCC-FANCE-FANCF-FANCG protein complex, as well as the presence of RMI1. {ECO:0000269|PubMed:15257300, ECO:0000269|PubMed:15775963}.

Disease: Bloom syndrome (BLM) [MIM:210900]: An autosomal recessive disorder. It is characterized by proportionate pre- and postnatal growth deficiency, sun-sensitive telangiectatic hypo- and hyperpigmented skin, predisposition to malignancy, and chromosomal instability. {ECO:0000269|PubMed:10862105, ECO:0000269|PubMed:7585968, ECO:0000269|PubMed:9285778}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the helicase family. RecQ subfamily. {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:		ATP-dependent DNA helicase that unwinds single- and double- stranded DNA in a 3'-5' direction (PubMed:9388193, PubMed:24816114, PubMed:25901030). Participates in DNA replication and repair (PubMed:12019152, PubMed:21325134, PubMed:23509288). Involved in 5'-end resection of DNA during double-strand break (DSB) repair: unwinds DNA and recruits DNA2 which mediates the cleavage of 5'-ssDNA (PubMed:21325134). Negatively regulates sister chromatid exchange (SCE) (PubMed:25901030). Stimulates DNA 4-way junction branch migration and DNA Holliday junction dissolution (PubMed:25901030). Binds single- stranded DNA (ssDNA), forked duplex DNA and DNA Holliday junction (PubMed:20639533, PubMed:24257077, PubMed:25901030). Recruited by the KHDC3L-OOEP scaffold to DNA replication forks where it is retained by TRIM25 ubiquitination, it thereby promotes the restart of stalled replication forks (By similarity). {ECO:0000250\|UniProtKB:O88700, ECO:0000269\|PubMed:12019152, ECO:0000269\|PubMed:20639533, ECO:0000269\|PubMed:21325134, ECO:0000269\|PubMed:23509288, ECO:0000269\|PubMed:24257077, ECO:0000269\|PubMed:24816114, ECO:0000269\|PubMed:25901030, ECO:0000269\|PubMed:9388193}.


Catalytic activity:		Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.12; Evidence={ECO:0000269\|PubMed:24816114, ECO:0000269\|PubMed:25901030};
Cofactor:		Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269\|PubMed:24816114, ECO:0000269\|PubMed:25901030}; Note=Binds 1 zinc ion per subunit. {ECO:0000269\|PubMed:24816114, ECO:0000269\|PubMed:25901030};
Subunit:		Monomer (PubMed:28228481). Homodimer (via N-terminus) (PubMed:28228481). Homotetramer (via N-terminus); dimer of dimers (PubMed:28228481). Homohexamer (via N-terminus) (PubMed:28228481). Self-association negatively regulates DNA unwinding amplitude and rate. Oligomeric complexes dissociate into monomer in presence of ATP (PubMed:28228481). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with RMI complex. Interacts directly with RMI1 (via N-terminal region) component of RMI complex. Found in a complex, at least composed of BLM, RAD51 and SPIDR; the complex formation is mediated by SPIDR. Interacts with the KHDC3L/FILIA- OOEP/FLOPED scaffold complex and TRIM25 at DNA replication forks (By similarity). Interacts with ubiquitinated FANCD2 (PubMed:15257300). Interacts with SUPV3L1 (PubMed:17961633). Interacts with TOP3A (via N- terminal region). Interacts with SPIDR (via C-terminal region); the interaction is direct and required to target BLM to sites of DNA damage. {ECO:0000250\|UniProtKB:O88700, ECO:0000269\|PubMed:15257300, ECO:0000269\|PubMed:15775963, ECO:0000269\|PubMed:16595695, ECO:0000269\|PubMed:17961633, ECO:0000269\|PubMed:18923082, ECO:0000269\|PubMed:18923083, ECO:0000269\|PubMed:21325134, ECO:0000269\|PubMed:23509288, ECO:0000269\|PubMed:28228481}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:23509288}. Note=Together with SPIDR, is redistributed in discrete nuclear DNA damage-induced foci following hydroxyurea (HU) or camptothecin (CPT) treatment. Accumulated at sites of DNA damage in a RMI complex- and SPIDR-dependent manner.
Domain:		The N-terminal region mediates dimerization and homooligomerization (PubMed:28228481). Both the helicase ATP-binding domain and the helicase C-terminal domain form intramolecular interactions with the HRDC domain in a ATP-dependent manner (PubMed:25901030). The HRDC domain is required for single-stranded DNA (ssDNA) and DNA Holliday junction binding (PubMed:20639533). {ECO:0000269\|PubMed:20639533, ECO:0000269\|PubMed:25901030, ECO:0000269\|PubMed:28228481}.
Ptm:		Poly-ubiquitinated by TRIM25 at Lys-259. {ECO:0000250\|UniProtKB:O88700}.
Ptm:		Phosphorylated in response to DNA damage. Phosphorylation requires the FANCA-FANCC-FANCE-FANCF-FANCG protein complex, as well as the presence of RMI1. {ECO:0000269\|PubMed:15257300, ECO:0000269\|PubMed:15775963}.
Disease:		Bloom syndrome (BLM) [MIM:210900]: An autosomal recessive disorder. It is characterized by proportionate pre- and postnatal growth deficiency, sun-sensitive telangiectatic hypo- and hyperpigmented skin, predisposition to malignancy, and chromosomal instability. {ECO:0000269\|PubMed:10862105, ECO:0000269\|PubMed:7585968, ECO:0000269\|PubMed:9285778}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the helicase family. RecQ subfamily. {ECO:0000305}.