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FLASH GENE
Symbol BRCA1 contributors: mct/shn - updated : 03-06-2013
HGNC name breast cancer 1, early onset
HGNC id 1100
Corresponding disease
BRCA1 hereditary breast/ovarian cancer
Location 17q21.31      Physical location : 41.196.312 - 41.277.500
Synonym name
  • BRCA1/BRCA2-containing complex, subunit 1
  • RING finger protein 53
  • breast and ovarian cancer susceptibility protein 1
  • breast and ovarian cancer sususceptibility protein 1
  • breast cancer type 1 susceptibility protein
  • protein phosphatase 1, regulatory subunit 53
  • Synonym symbol(s) RNF53, BRCC1, PSCP, BRCAI, IRIS, BROVCA1, PPP1R53, PNCA4
    EC.number 6.3.2.-
    DNA
    TYPE functioning gene
    STRUCTURE 81.19 kb     23 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Binding site   transcription factor
    motif repetitive sequence   ALU
    text structure
  • TATA less, several binding sites for transcription factors
  • an AUG triplet upstream exon 1b, high density of Alu repetitive DNA
  • two evolutionarily conserved noncoding sequences (CNS1 and 2) in intron 2, 5 kb downstream of the core BRCA1 promoter, having differential transcriptional regulatory activity in epithelial cell lines
  • promoter is regulated by a variety of stimuli, including estrogen stimulation, DNA damage and hypoxia
  • active control of chromatin marks, DNA accessibility and gene expression at the BRCA1 promoter by a'metabolic switch' provides an important molecular link between caloric intake and tumor suppressor expression in mammary cells
  • MAPPING cloned Y linked Y status confirmed
    Map cen - D17S1793 - D17S1801 - BRCA1 BRCA1 - D17S1789 - D17S951 - qter
    Physical map
    NAGLU 17q21.1 N-acetylglucosaminidase, alpha- (Sanfilippo disease IIIB) HSD17BP1 17q11-q21 hydroxysteroid (17-beta) dehydrogenase pseudogene 1 HSD17B1 17q21.1 hydroxysteroid (17-beta) dehydrogenase 1 DPCK 17q12-q21 bifunctional phosphopantetheine adenylyl transferase/dephospho CoA kinase TCFL4 17q21.1 transcription factor-like 4 HUMGT198A 17q12-q21 GT198, complete ORF LOC162427 17q21.31 hypothetical protein LOC162427 TUBG1 17q21 tubulin, gamma 1 LOC342578 17q21.31 similar to high mobility group protein homolog HMG4 TUBG2 17q21 tubulin, gamma 2 FLJ21019 17q21.31 hypothetical protein FLJ21019 GPR2 17q21.1 G protein-coupled receptor 2 CNTNAP1 17q21 contactin associated protein 1 EZH1 17q21 enhancer of zeste homolog 1 (Drosophila) RAMP2 17q12-q21.1 receptor (calcitonin) activity modifying protein 2 MGC10540 17q21.31 hypothetical protein MGC10540 PRKWNK4 17q12 protein kinase, lysine deficient 4 HSPC009 17q21 HSPC009 protein FLJ40137 17q21.31 hypothetical protein FLJ40137 BECN1 17q21 beclin 1 (coiled-coil, myosin-like BCL2 interacting protein) PSME3 17q21 proteasome (prosome, macropain) activator subunit 3 (PA28 gamma; Ki) AOC2 17q21 amine oxidase, copper containing 2 (retina-specific) AOC3 17q21 amine oxidase, copper containing 3 (vascular adhesion protein 1) LOC90586 17q21.31 amine oxidase pseudogene LOC388387 17 hypothetical gene supported by AK055784 G6PC 17q21 glucose-6-phosphatase, catalytic (glycogen storage disease type I, von Gierke disease) MGC2744 17q21.31 hypothetical protein MGC2744 DKFZp761H0421 17q21.31 hypothetical protein DKFZp761H0421 RPL27 17q21 ribosomal protein L27 IFI35 17q21 interferon-induced protein 35 VAT1 17q21 vesicle amine transport protein 1 homolog (T californica) ARHN 17q21 ras homolog gene family, member N BRCA1 17q21 breast cancer 1, early onset RPL21P4 17q21 ribosomal protein L21 pseudogene 4 NBR2 17q21 neighbor of BRCA1 gene 2 LOC387620 17 membrane component, chromosome 17, surface marker 2 MGC20235 17q21.31 hypothetical protein MGC20235 LOC388388 17 LOC388388 RNU2P2 17q21.31 RNA, U2 small nuclear pseudogene 2
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    23 splicing initiation site 7224 207.7 1863 . widely . nuclear 2006 16460311
    isoform 1
    18 splicing initiation site 7287 207.7 1884 - 2006 16460311
  • BRCA1-delta14-18
  • isoform 2
  • 15 splicing 7132 - 1816 . widely . reduced or absent in several breast and ovarian cancer cell lines . cytoplasmic 2006 16460311
  • BRCA1-delta2-10
  • isoform 3
  • 20 splicing 3699 - 759 - 2006 16460311
  • BRCA1-delta9-11
  • isoform 4
  • 19 splicing 3800 - 699 cytoplasmic 2006 16460311
  • BRCA1-delta14-17
  • isoform 5
  • 23 splicing 7128 - - - -
    non-coding RNA
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticthymus   highly
    Nervousbrainhindbraincerebellum highly Homo sapiens
     brainlimbic systemhippocampusdentate gyrushighly Homo sapiens
    Reproductivefemale systemovary   
     female systembreast   
     male systemtestis  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialsecretoryglandular  
    Lymphoid    
    cells
    SystemCellPubmedSpeciesStageRna symbol
     epithelial cell
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo
    Text
  • high levels of BRCA1 expression have been found in the embryonic neuroectoderm
  • PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal RING zinc finger domain, and N-terminus of BRCA1 harbors a degron sequence that is sufficient and necessary for conferring BRCA1 degradation
  • a sequence homology in the C terminal part, with the putative consensus sequence of granin family
  • two BRCT adaptor domains BRCTN and BRCTC, BRCA C terminus (BRCT) motifs that form a phosphoprotein recognition domain, and BRCT phosphoprotein recognition, but not the E3 ligase activity, is required for BRCA1 tumor suppression
  • a tandem repeat of the BRCT domain (BRCT-tan), playing a critical role in BRCA1-mediated tumour suppression, and are phospho-serine/threonine recognition modules essential for the function of BRCA1
  • an N-terminal nuclear export sequence (NES)
  • a C-terminal fragment that is unstable in cells as it is targeted for degradation by the N-end rule pathway, and is stable in cells lacking ATE1, a component of the N-end rule pathway
  • a gamma-tubulin-binding domain
  • conjugated PhosphoP
    HOMOLOGY
    interspecies ortholog to Brca1, Rattus norvegicus
    ortholog to Brca1, Mus musculus
    ortholog to BRCA1, Pan troglodytes
    Homologene
    FAMILY
    CATEGORY regulatory , transcription factor , tumor suppressor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus,chromatin/chromosome
    text
  • nucleus in normal cells, intranuclear foci formation induced by interaction with BARD1
  • N terminus and C-terminal BRCT domains is sufficient to mediate effective BRCA1 targeting to the centrosome
  • BCL2 and BRCA1 colocalized to mitochondria and endoplasmic reticulum in a process requiring the TM domain of BCL2
  • basic FUNCTION
  • involved in the dynamics of the mitotic spindle and in the segregation of duplicated chromosomes
  • negative regulator of mammary cell growth (in a RB-dependent fashion)
  • activating DNA repair through homologous recombination, in cooperation with BRCA2, RAD51 and RAD52, P-BRCA
  • playing a significant role by its ubiquitin ligase activity in tumour suppression
  • regulating the G2/M checkpoint by activating CHEK1 upon DNA damage
  • complexing with RNA polymerase II holoenzyme and involved in the regulation of hol-pol function
  • recruiting CREBBP/EP300 and interacting with components of the histone deacetylase complex in cooperation with STAT1
  • mediating ubiquitin-conjugating enzyme (E2)-dependent ubiquitination through the RING finger domain (ubiquitin protein ligase activity)
  • induction of BRCA1 triggers JNK/SAPK (MAPK8) dependent apoptosis through induction of DDIT1 (GADD45)
  • transcriptional control through modulation of chromatin structure
  • having critical function in the proliferation and differentiation of neural progenitor cells
  • is required for the proliferative effects of EZH2
  • required for appropriate cell cycle arrests after ionizing irradiation
  • involved in transcriptional regulation of P21 in response to DNA damage
  • exerts transcriptional repression through interaction with RBBP8 in the C-terminal BRCT domain and ZNF350 in the central domain)
  • involved in regulation of lipid biosynthesis through its inhibition of ACACA activity, which could be a novel tumor suppressor function of BRCA1
  • required for FANCD2 targeting to sites of DNA damage
  • inhibits lipid synthesis by binding to inactive phosphorylated ACACA and preventing its dephosphorylation
  • recruited to the telomere in a Rad50-dependent manner and may regulate telomere length and stability, in part through its presence at the telomere
  • UIMC1/BRCA1 complex, is required for efficient BRCA1 focal recruitment, and suppress excessive DSB (DNA double-strand breaks) end processing, homologous recombination-type DSB repair, and overt chromosomal instability
  • function of BRCA1 in the control of centriole pairing
  • required for postreplication repair after UV-induced DNA damage
  • role of BRCA1 in maintaining global heterochromatin integrity accounts for many of its tumour suppressor functions
  • BRCA1 and its ubiquitin E3 ligase activity are required for gene silencing in constitutive heterochromatin
  • ubiquitin ligase activity of BRCA1 is essential for the maintenance of the ubiquityl-histone H2A mark within constitutive heterochromatic regionsin human cells derived from breast cancers
  • multifunctional protein that also ubiquitinates TUBG1 and, consequently, inhibits microtubule nucleation at the centrosome
  • epigenetically represses MIR155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the MIR155 promoter
  • functions independently of homologous recombination in DNA interstrand crosslink repair
  • novel functions of BRCA1 in miRNA biogenesis, which may be linked to its tumor suppressor mechanism and maintenance of genomic stability
  • tripartite regulation of homologous recombination by RNF8, BRCA1, and TP53BP1
  • nuclear tumor suppressor that is critical for resolving double-strand DNA breaks (DSBs) and interstrand crosslinks (ICLs) by homologous recombination (HR)
  • BRCA1 and HSP90AA1 cooperate in homologous and non-homologous DNA double-strand-break repair and G2/M checkpoint activation
  • role of BRCA1 in regulating damage-associated checkpoint and repair responses to HSP90AA1 inhibitors
  • BRCA1 E3 ligase activity regulates the G2/M cell cycle checkpoint and, thus, contributes to maintenance of genomic stability
  • BRCA1 and TP53BP1 play decisive roles in the choice of DNA double-strand break repair mechanisms
  • BRCA1, FANCD2 and CHEK1 are potential targets for the modulation of radiation response in bystander cells
  • CELLULAR PROCESS cell cycle
    cell life, cell death/apoptosis
    nucleotide, repair
    nucleotide, genomic integrity
    nucleotide, transcription
    protein, ubiquitin dependent proteolysis
    PHYSIOLOGICAL PROCESS development
    text regulator of gene stability (caretaker)
    PATHWAY
    metabolism lipid/lipoprotein
    signaling
    chromosome instability pathway
    a component
  • heterodimer with BARD1 containing a ubiquitin ligase activity that is important for prevention of breast and ovarian cancer and inducing the formation of conjugated ubiquitin structures during DNA replication and repair
  • BRCA1, CCDC98 and UIMC1 form a functional complex and participate in the DNA damage response
  • BRCA1/BARD1 may promote genome stability and tumor suppression through its involvement in other cellular processes, such as mitotic spindle assembly and cell cycle checkpoint control
  • BRCA1/E2F1/RBBP8 binding to ATM promoter activates ATM transcription
  • INTERACTION
    DNA
  • promoter regions of CYP1A1 and CYP1B1
  • inactive X chromosome
  • RNA
  • XIST RNA
  • small molecule metal binding,
  • Zn2+ binding
  • protein
  • importin-alpha subunit of the nuclear transport signal receptor
  • Rad51
  • p32 and p65 BRCA1 interacting proteins, cyclin A, cyclin B1, cyclin D1, cdc2, cdk2 and E2F
  • BRAP2
  • BAP1
  • p53
  • a component of the RNA polymerase II (Pol II) holoenzyme
  • BRCA2
  • c-Myc
  • CtIP
  • gamma-tubulin
  • CtBP
  • RbAp46 and RbAp48, HDAC1 and HDAC2
  • hRad50-hMre11-p95 complex
  • hypophosphorylated form of pRb
  • CBP/p300
  • BRCA1-associated genome surveillance complex: MSH2, MSH6, MLH1, ATM, BLM, and the RAD50-MRE11-NBS1 protein complex, and DNA replication factor C, RFC
  • RNA polymerase II
  • STAT1
  • valosin-containing protein, VCP
  • ZBRK1
  • ATF1
  • androgen receptor, AR and p160
  • checkpoint kinase ATR
  • JAK1 and JAK2
  • FANCD2
  • BACH1
  • retinoblastoma suppressor (Rb)-associated protein 46, RbAp46
  • c-Fos oncogene regulator Elk-1
  • LMO4
  • GADD45
  • N-Myc-interacting protein, Nmi
  • c-Abl
  • JUNB and JUND
  • alpha- and beta-tubulin
  • Fanconi anemia protein, FANCA
  • Acetyl Coenzyme A (CoA) Carboxylase alpha, ACCA
  • ER-alpha
  • Stat5a
  • phosphatase 1alpha, PP1alpha
  • Sp1
  • p65/RelA
  • four and a half LIM-only protein 2, FHL2
  • BARD1/BRCC45/BRCC36
  • IFI16
  • p53
  • Aurora-A
  • FHL2
  • zinc-finger-containing protein NUFIP
  • nucleolar phosphoprotein nucleophosmin/B23, NPM
  • SWI/SNF enzymes
  • mitogen-activated protein kinase (MAPK) kinase kinase 3, MEKK3
  • TRAP220
  • Cdk-activating kinase, CAK
  • Smad3
  • hGCN5, TRRAP, and hMSH2/6
  • poly(A)-binding protein 1, PABP
  • cyclin D1
  • Abraxas and RAP80
  • TR-interacting protein, ATRIP
  • CCDC98
  • aryl hydrocarbon receptor, AhR
  • ERK1/2
  • p14ARF
  • Ku80
  • vitamin D receptor, VDR
  • Rap80
  • NBA1
  • Mediator of Rap80 Interactions and Targeting 40 kd, MERIT40
  • PALB2
  • NINL (
  • centrosomal protein Nlp
  • E2s
  • deleted in breast cancer 1, DBC1/KIAA1967
  • FANCJ
  • BRD7
  • MRG15
  • UBXN1
  • HERC2
  • UE2I
  • TFII-I
  • BCL2
  • KIAA0101
  • YY1 binds to the promoter of BRCA1, and its overexpression resulted in increased expression of BRCA1 and a number of BRCA1 downstream genes
  • Cockayne syndrome B, CSB
  • BARD1
  • AP2-alpha, PAX2 and ZF5
  • CDK1
  • GATA3
  • gamma tubulin, CRM1, and Aurora A
  • BRCA1 antagonises TP53BP1-dependent DNA repair in S phase by inhibiting its interaction with chromatin proximal to damage sites
  • claspin (
  • SKP1 regulates BRCA1 protein stability
  • FBXO44 is an important protein that influences BRCA1 protein level
  • BRCA1 heterodimerizes with its partner protein, BARD1, via the RING domain present in both proteins
  • BRCA1-dependent degradation of cyclin B and CDC25C is reversed by proteasome inhibitors and is enhanced following DNA damage, which may represent a possible mechanism to prevent cyclin B and CDC25C accumulation, a requirement for mitotic entry
  • BRCA1 downregulates the kinase activity of PLK1 by modulating the dynamic interactions of AURKA, BORA, and PLK1
  • TP53BP1 recruitment requires the direct recognition of a DSB-specific histone code and its influence on pathway choice is mediated by mutual antagonism with BRCA1
  • cell & other
  • SWI/SNF chromatin remodeling complex through SMARCA4
  • associated with the centrosome during mitosis
  • REGULATION
    repressed by
  • LMO4 in association with RBBP8 in breast tissue
  • CTBP1 (represses BRCA1 transcription by binding to the E2F4 site of the BRCA1 promoter)
    Brg-1 and ets-2
    Phosphorylated by ataxia telangiectasia mutated protein-related protein kinase, ATR
    CDK2-cyclin A or E
    casein kinase 2, CK2
    heregulin
    regulated by Cds1 kinase (hCds1/Chk2)
    Other
  • nuclear cell cycle regulated phosphoprotein of breast epithelium
  • phosphorylated by ATM protein kinase in response to ionizing radiation induced DNA damage,regulating the expression of GADD45s and CDLN1A
  • potentiated by binding JUNB to one of the transactivation domain of BRCA1
  • CAV1 enhances BRCA1 protein and mRNA levels
  • regulated by UBXN1 (regulates the enzymatic function of BRCA1 in a manner that is dependent on its ubiquitination status)
    hypoxia is a driving force for long-term silencing of BRCA1, thereby promoting genome instability and tumor progression
    regulated by Cds1 kinase (hCds1/Chk2)
    methylated by PRMT1
    negatively regulated by SUMO1
    Ubiquitinated and downregulated by ubiquitin-conjugating enzyme E2T
    ASSOCIATED DISORDERS
    corresponding disease(s) BRCA1
    related resource Breastcancer
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    or loss of function in breast, ovarian carcinomas (sporadic or not)
    tumoral germinal mutation      
    increased risk of Prostate carcinoma in men
    constitutional     --over  
    in proliferative cells
    tumoral germinal mutation     loss of function
    in patients with primary ovarian, fallopian tube, or peritoneal cancers
    tumoral       loss of function
    BRCA1 loss activates CTSL1-mediated degradation of TP53BP1
    Susceptibility to breast cancer
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    clinically relevant target for enhancing sensitivity in refractory and/or resistant malignancies
    cancer  
    MIR155 is a potential therapeutic target for BRCA1-deficient tumors
    cancermetastases 
    Treatment of Brca1/p53-deficient mice with the progesterone antagonist mifepristone (RU 486) prevented mammary tumorigenesis
    ANIMAL & CELL MODELS
  • mice homozygous for the mutant BRCA1 allele died in utero between 10 and 13 days of gestation due to abnormalities in the neural tube, spina bifida and anencephaly
  • Brca1+/- mice are normal and fertile and lack tumors by age eleven months, while Brca1-/- mice die before day 7.5 of embryogenesis due to a failure of the proliferative burst
  • Brca1-deficient mouse embryonic stem cells have impaired repair of chromosomal DNA double-strand breaks by homologous recombination
  • impact of the Brca1 or Brca2 null mutation is less severe in a p53 null background
  • mice deficient in the Brca1 exon 11 isoform (Brca1Delta11/Delta11) died late in gestation because of widespread apoptosis
  • most female Brca1Delta11/Delta11 Trp53+/- mice develop mammary tumors with loss of the remaining Trp53 allele within 6-12 months
  • Brca1(Delta11/Delta11)Gadd45a(-/-) embryos at embryonic days 9.5-10.5 were exencephalic and exhibited a high incidence of apoptosis accompanied by altered levels of BAX, BCL-2, and p53