BRCA1_CAEEL
ID BRCA1_CAEEL Reviewed; 612 AA.
AC B6VQ60; B6VQ61;
DT 20-DEC-2017, integrated into UniProtKB/Swiss-Prot.
DT 16-DEC-2008, sequence version 1.
DT 03-AUG-2022, entry version 107.
DE RecName: Full=Breast cancer type 1 susceptibility protein homolog {ECO:0000250|UniProtKB:P38398};
DE EC=2.3.2.27 {ECO:0000269|PubMed:16628214};
DE AltName: Full=RING-type E3 ubiquitin transferase BRCA1 {ECO:0000250|UniProtKB:P38398};
GN Name=brc-1 {ECO:0000303|PubMed:14711411, ECO:0000312|WormBase:C36A4.8a};
GN ORFNames=C36A4.8 {ECO:0000312|WormBase:C36A4.8a};
OS Caenorhabditis elegans.
OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC Caenorhabditis.
OX NCBI_TaxID=6239 {ECO:0000312|Proteomes:UP000001940};
RN [1] {ECO:0000312|Proteomes:UP000001940}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Bristol N2 {ECO:0000312|Proteomes:UP000001940};
RX PubMed=9851916; DOI=10.1126/science.282.5396.2012;
RG The C. elegans sequencing consortium;
RT "Genome sequence of the nematode C. elegans: a platform for investigating
RT biology.";
RL Science 282:2012-2018(1998).
RN [2] {ECO:0000305}
RP FUNCTION, INTERACTION WITH BRD-1, AND DISRUPTION PHENOTYPE.
RX PubMed=14711411; DOI=10.1016/j.cub.2003.11.029;
RA Boulton S.J., Martin J.S., Polanowska J., Hill D.E., Gartner A., Vidal M.;
RT "BRCA1/BARD1 orthologs required for DNA repair in Caenorhabditis elegans.";
RL Curr. Biol. 14:33-39(2004).
RN [3] {ECO:0000305}
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PATHWAY, UBIQUITINATION,
RP IDENTIFICATION IN CEBCD COMPLEX WITH BRD-1; RAD-51 AND LET-70, SUBUNIT,
RP SUBCELLULAR LOCATION, PHOSPHORYLATION, AND DISRUPTION PHENOTYPE.
RX PubMed=16628214; DOI=10.1038/sj.emboj.7601102;
RA Polanowska J., Martin J.S., Garcia-Muse T., Petalcorin M.I.R.,
RA Boulton S.J.;
RT "A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA
RT damage sites.";
RL EMBO J. 25:2178-2188(2006).
RN [4] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=18219312; DOI=10.1038/sj.embor.7401167;
RA Adamo A., Montemauri P., Silva N., Ward J.D., Boulton S.J., La Volpe A.;
RT "BRC-1 acts in the inter-sister pathway of meiotic double-strand break
RT repair.";
RL EMBO Rep. 9:287-292(2008).
RN [5] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=19646877; DOI=10.1016/j.cub.2009.06.045;
RA Pontier D.B., Tijsterman M.;
RT "A robust network of double-strand break repair pathways governs genome
RT integrity during C. elegans development.";
RL Curr. Biol. 19:1384-1388(2009).
RN [6] {ECO:0000305}
RP FUNCTION.
RX PubMed=20207739; DOI=10.1074/jbc.m110.107011;
RA Koon J.C., Kubiseski T.J.;
RT "Developmental arrest of Caenorhabditis elegans BRAP-2 mutant exposed to
RT oxidative stress is dependent on BRC-1.";
RL J. Biol. Chem. 285:13437-13443(2010).
RN [7] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24424777; DOI=10.1534/genetics.113.158295;
RA Wolters S., Ermolaeva M.A., Bickel J.S., Fingerhut J.M., Khanikar J.,
RA Chan R.C., Schumacher B.;
RT "Loss of Caenorhabditis elegans BRCA1 promotes genome stability during
RT replication in smc-5 mutants.";
RL Genetics 196:985-999(2014).
RN [8] {ECO:0000305}
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=26903030; DOI=10.14348/molcells.2016.2206;
RA Park S., Choi S., Ahn B.;
RT "DNA strand breaks in mitotic germ cells of Caenorhabditis elegans
RT evaluated by comet assay.";
RL Mol. Cells 39:204-210(2016).
RN [9]
RP FUNCTION, INTERACTION WITH MSH-5 AND SYP-3, SUBCELLULAR LOCATION, AND
RP DISRUPTION PHENOTYPE.
RX PubMed=30383754; DOI=10.1371/journal.pgen.1007653;
RA Janisiw E., Dello Stritto M.R., Jantsch V., Silva N.;
RT "BRCA1-BARD1 associate with the synaptonemal complex and pro-crossover
RT factors and influence RAD-51 dynamics during Caenorhabditis elegans
RT meiosis.";
RL PLoS Genet. 14:e1007653-e1007653(2018).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that specifically mediates the
CC formation of polyubiquitin chains and plays a central role in DNA
CC repair (PubMed:16628214). Plays a role in triggering cellular responses
CC at damage sites in response to DNA damage that may be induced by UV and
CC ionizing radiation for example (PubMed:14711411, PubMed:16628214,
CC PubMed:24424777, PubMed:26903030, PubMed:30383754). Functions in
CC double-strand break repair, and is required for homologous
CC recombination between sister chromatids in meiotic and mitotic cells
CC (PubMed:18219312, PubMed:19646877, PubMed:24424777, PubMed:26903030).
CC In particular, protects against chromosome non-disjunction and nuclear
CC fragmentation during meiotic double-strand break repair to ensure
CC sister chromatid recombination and aid chromosome stability
CC (PubMed:14711411, PubMed:18219312, PubMed:24424777). Required for
CC normal cell cycle progression (PubMed:20207739). Along with brap-2
CC modulates the expression of cell cycle arrest protein cki-1 in response
CC to increased levels of reactive oxygen species (PubMed:20207739).
CC Constituent of the CeBCD complex that possesses E3 ubiquitin-protein
CC ligase activity (PubMed:14711411). When bound to chromatin, the brc-1-
CC brd-1 heterodimer within the CeBCD complex is inactive during normal
CC conditions, but in response to DNA damage, the brc-1-brd-1 heterodimer
CC associates with other proteins such as the recombinase rad-51 or the
CC E2-ubiquitin-conjugating enzyme let-70, which activate the CeBCD
CC complex as an E3-ubiquitin ligase (PubMed:16628214). Moreover,
CC association between the brc-1-brd-1 heterodimer and rad-51 and let-70,
CC probably requires DNA checkpoint proteins such as atl-1 and mre-11 in
CC order to induce ubiquitination at DNA damage sites (PubMed:16628214).
CC To this end, the brc-1-brd-1 heterodimer coordinates a diverse range of
CC cellular pathways such as DNA damage repair, ubiquitination and
CC transcriptional regulation to maintain genomic stability
CC (PubMed:14711411). {ECO:0000269|PubMed:14711411,
CC ECO:0000269|PubMed:16628214, ECO:0000269|PubMed:18219312,
CC ECO:0000269|PubMed:19646877, ECO:0000269|PubMed:20207739,
CC ECO:0000269|PubMed:24424777, ECO:0000269|PubMed:26903030,
CC ECO:0000269|PubMed:30383754}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:16628214};
CC -!- ACTIVITY REGULATION: E3 ubiquitin-protein ligase activity of CeBCD
CC complexes occurs at DNA damage sites. Following DNA damage, E3
CC ubiquitin-protein ligase activity is reduced by caffeine treatment
CC (inhibitor of ATM and ATK kinase activity).
CC {ECO:0000269|PubMed:16628214}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:16628214}.
CC -!- SUBUNIT: Heterodimer (via RING-type zinc finger) with brd-1 to form the
CC core CeBCD complex (PubMed:14711411, PubMed:16628214). Brc-1-brd-1
CC heterodimer-containing CeBCD complexes bound to chromatin are activated
CC as an E3-ubiquitin ligase in response to DNA damage (PubMed:16628214).
CC The heterodimer interacts with the recombinase rad-51 following
CC ionizing irradiation; the interaction is direct (PubMed:16628214). The
CC heterodimer interacts the E2-ubiquitin-conjugating enzyme let-70
CC following ionizing irradiation (PubMed:16628214). The heterodimer
CC interacts with the pro-crossover proteins msh-5 and syp-3
CC (PubMed:30383754). {ECO:0000269|PubMed:14711411,
CC ECO:0000269|PubMed:16628214, ECO:0000269|PubMed:30383754}.
CC -!- INTERACTION:
CC B6VQ60; Q21209: brd-1; NbExp=4; IntAct=EBI-3895496, EBI-3895480;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16628214,
CC ECO:0000269|PubMed:30383754}. Chromosome {ECO:0000269|PubMed:16628214,
CC ECO:0000269|PubMed:30383754}. Cytoplasm {ECO:0000269|PubMed:16628214}.
CC Note=Mainly localizes to the nucleus and a small proportion is
CC chromatin bound (PubMed:30383754). Co-localizes with brd-1 in germline
CC nuclei at meiotic prophase I (PubMed:30383754). At the transition
CC between mid- and late- pachytene, localization together with brd-1 is
CC less diffuse and becomes a linear pattern along the chromosomes
CC (PubMed:30383754). In late pachytene nuclei, co-localizes with brd-1
CC and syp-1 at crossover sites and the short arm of the bivalent
CC (PubMed:30383754). Co-localizes with the pro-crossover factors cosa-1,
CC zhp-3 and msh-5 at crossover sites in mid-late pachytene nuclei
CC (PubMed:30383754). Co-localizes with plk-2 in pachytene nuclei
CC (PubMed:30383754). Localizes to DNA damage sites on chromatin following
CC DNA damage. {ECO:0000269|PubMed:16628214, ECO:0000269|PubMed:30383754}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=a {ECO:0000312|WormBase:C36A4.8a};
CC IsoId=B6VQ60-1; Sequence=Displayed;
CC Name=b {ECO:0000312|WormBase:C36A4.8b};
CC IsoId=B6VQ60-2; Sequence=VSP_059259;
CC -!- PTM: Phosphorylation of CeBCD complexes is required for E3 ubiquitin-
CC protein ligase activity. {ECO:0000269|PubMed:16628214}.
CC -!- DISRUPTION PHENOTYPE: Animals are viable (PubMed:18219312,
CC PubMed:19646877). However, there is defective double strand break
CC repair (PubMed:18219312, PubMed:19646877, PubMed:26903030). During the
CC early stages of meiosis, this is characterized by impaired homologous
CC recombination in germ cells with increased apoptosis and increased
CC numbers of rad-51-positive foci (PubMed:18219312, PubMed:19646877).
CC Increased sensitivity to UV and IR irradiation and topoisomerase
CC inhibitor camptothecin compared to wild-type (PubMed:24424777,
CC PubMed:26903030). Following either IR irradiation or camptothecin
CC treatment, there is reduced egg hatching (PubMed:26903030).
CC Furthermore, there are also DNA damage repair defects following
CC ionizing radiation and UV irradiation characterized by reduced
CC ubiquitination at DNA damage sites and reduced rad-51-positive foci,
CC respectively (PubMed:16628214, PubMed:24424777, PubMed:26903030). High
CC levels of embryonic lethality and abolished brd-1 expression following
CC DNA damage induced by ionising radiation (PubMed:30383754). Double
CC knockout with brd-1 impairs rad-51 localization to DNA damage sites
CC following DNA damage induced by ionising radiation (PubMed:30383754).
CC RNAi-mediated knockdown results in high X chromosome non-disjunction
CC leading to a high incidence of males (him) phenotype (PubMed:14711411).
CC RNAi-mediated knockdown in addition to gamma-irradiation at the L4
CC stage of larval development, results in reduced progeny, increased cep-
CC 1/p53-dependent germ cell death, chromosome fragmentation and DNA
CC repair defects (PubMed:14711411). {ECO:0000269|PubMed:14711411,
CC ECO:0000269|PubMed:16628214, ECO:0000269|PubMed:18219312,
CC ECO:0000269|PubMed:19646877, ECO:0000269|PubMed:24424777,
CC ECO:0000269|PubMed:26903030, ECO:0000269|PubMed:30383754}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; BX284603; CAR97812.1; -; Genomic_DNA.
DR EMBL; BX284603; CAR97813.1; -; Genomic_DNA.
DR RefSeq; NP_001254881.1; NM_001267952.1.
DR RefSeq; NP_001254882.1; NM_001267953.1. [B6VQ60-2]
DR AlphaFoldDB; B6VQ60; -.
DR SMR; B6VQ60; -.
DR ComplexPortal; CPX-375; brc-1/brd-1 complex.
DR IntAct; B6VQ60; 1.
DR STRING; 6239.C36A4.8a; -.
DR EPD; B6VQ60; -.
DR PaxDb; B6VQ60; -.
DR PeptideAtlas; B6VQ60; -.
DR EnsemblMetazoa; C36A4.8a.1; C36A4.8a.1; WBGene00000264.
DR EnsemblMetazoa; C36A4.8b.1; C36A4.8b.1; WBGene00000264. [B6VQ60-2]
DR GeneID; 175499; -.
DR CTD; 175499; -.
DR WormBase; C36A4.8a; CE43190; WBGene00000264; brc-1. [B6VQ60-1]
DR WormBase; C36A4.8b; CE43228; WBGene00000264; brc-1. [B6VQ60-2]
DR eggNOG; KOG4362; Eukaryota.
DR GeneTree; ENSGT00440000034289; -.
DR HOGENOM; CLU_446355_0_0_1; -.
DR InParanoid; B6VQ60; -.
DR OMA; SHVWELP; -.
DR OrthoDB; 472443at2759; -.
DR UniPathway; UPA00143; -.
DR PRO; PR:B6VQ60; -.
DR Proteomes; UP000001940; Chromosome III.
DR Bgee; WBGene00000264; Expressed in germ line (C elegans) and 4 other tissues.
DR GO; GO:0070531; C:BRCA1-A complex; IBA:GO_Central.
DR GO; GO:0031436; C:BRCA1-BARD1 complex; IDA:WormBase.
DR GO; GO:0005694; C:chromosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:WormBase.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IBA:GO_Central.
DR GO; GO:0006915; P:apoptotic process; IMP:WormBase.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IMP:WormBase.
DR GO; GO:0071479; P:cellular response to ionizing radiation; IMP:UniProtKB.
DR GO; GO:0006281; P:DNA repair; IMP:WormBase.
DR GO; GO:0000724; P:double-strand break repair via homologous recombination; IMP:WormBase.
DR GO; GO:0009792; P:embryo development ending in birth or egg hatching; IMP:UniProtKB.
DR GO; GO:0051307; P:meiotic chromosome separation; IMP:WormBase.
DR GO; GO:0000070; P:mitotic sister chromatid segregation; IGI:UniProtKB.
DR GO; GO:0045717; P:negative regulation of fatty acid biosynthetic process; IBA:GO_Central.
DR GO; GO:0035067; P:negative regulation of histone acetylation; IBA:GO_Central.
DR GO; GO:0006289; P:nucleotide-excision repair; IMP:WormBase.
DR GO; GO:1905168; P:positive regulation of double-strand break repair via homologous recombination; EXP:ComplexPortal.
DR GO; GO:0035066; P:positive regulation of histone acetylation; IBA:GO_Central.
DR GO; GO:2001022; P:positive regulation of response to DNA damage stimulus; EXP:ComplexPortal.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0016567; P:protein ubiquitination; IDA:WormBase.
DR Gene3D; 3.30.40.10; -; 1.
DR Gene3D; 3.40.50.10190; -; 2.
DR InterPro; IPR031099; BRCA1-associated.
DR InterPro; IPR001357; BRCT_dom.
DR InterPro; IPR036420; BRCT_dom_sf.
DR InterPro; IPR018957; Znf_C3HC4_RING-type.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR PANTHER; PTHR13763; PTHR13763; 2.
DR Pfam; PF16589; BRCT_2; 1.
DR Pfam; PF00097; zf-C3HC4; 1.
DR SMART; SM00292; BRCT; 2.
DR SMART; SM00184; RING; 1.
DR SUPFAM; SSF52113; SSF52113; 2.
DR PROSITE; PS50172; BRCT; 2.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell cycle; Chromosome; Cytoplasm; DNA damage;
KW DNA repair; Metal-binding; Nucleus; Reference proteome; Repeat;
KW Transferase; Zinc; Zinc-finger.
FT CHAIN 1..612
FT /note="Breast cancer type 1 susceptibility protein homolog"
FT /evidence="ECO:0000305"
FT /id="PRO_0000442581"
FT DOMAIN 415..477
FT /note="BRCT 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00033"
FT DOMAIN 505..603
FT /note="BRCT 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00033"
FT ZN_FING 21..61
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 140..173
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 142..167
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VAR_SEQ 1..495
FT /note="Missing (in isoform b)"
FT /evidence="ECO:0000305"
FT /id="VSP_059259"
SQ SEQUENCE 612 AA; 69718 MW; 159B448AEE153B8B CRC64;
MADVALRITE TVARLQKELK CGICCSTYKD PILSTCFHIF CRSCINACFE RKRKVQCPIC
RSVLDKRSCR DTYQITMAVQ NYLKLSEAFK KDIENMNTFK SLPPEKMFME SQMPLDITII
PENDGKRCAP DFAIPFLPVR RKRPSRPQPP SAFAEEPAEP VEPPEPATKQ PVELQSRVFP
LEKLKKDVET STETYKISRE ELKNVDIEEY INTLRENSTE IDEIDALFQL MPTMRQFLRN
NINQLMEKFH VAPPKKSEKP ANRRVSFASS QDLENIKIMT ASESLETPPE PIQKLAQKPE
VFKSTQNLID LNLNTAVKKP VVVASDDDEV VEDSEGELQI DEDDLANVTC ATSSTTLDAD
RTPKAIQDDE DRIDDELSQV PKTIVCSRIH NDADEVVGLE LLSDFYHKFL SNACRFAEDV
NEHTTHLVMM NSEGRSISQK STAYLYAIAR KCVIVGRQWL VDCITTGLLL SEADYTITSC
SSTIPVKIPP SIGSEMGWLR SRNDEHGKLF AGRRFMILRK FTMNPYFDYK QLIELVQQCG
GEILSCYENL SPEKLYIIFS KHSKAIEESK NIENLYKCDV VTMEWVLDSI SEYLILPTQP
YKAVDSIGCL QD
