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FLASH GENE
Symbol BRCA2 contributors: shn/mct - updated : 26-10-2016
HGNC name breast cancer 2, early onset
HGNC id 1101
Corresponding disease
BRCA2 hereditary breast/ovarian cancer
FANCB2 Fanconi anemia, complementation group B2
FANCD1 Fanconi anemia, complementation group D1
Location 13q13.1      Physical location : 32.889.616 - 32.973.809
Synonym name
  • BRCA1/BRCA2-containing complex, subunit 2
  • Fanconi anemia group D1 protein
  • Fanconi anemia, complementation group D1
  • breast cancer type 2 susceptibility protein
  • BRCA1/BRCA2-containing complex, subunit 2
  • breast and ovarian cancer susceptibility gene, early onset
  • Synonym symbol(s) BRC2, FAD, FAD1, FANCB, FANCD, BRCC2, BROVCA2, FACD, BRCC2, FANCD1, GLM3, PNCA2, XRCC11
    DNA
    TYPE functioning gene
    SPECIAL FEATURE head to head
    STRUCTURE 84.19 kb     27 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   transcription factor
    text structure three transcription factors activate (USF1, NFKB, and ELF1) and a single factor that represses (SNAI2) BRCA2 promoter activity
    MAPPING cloned Y linked   status provisional
    Map cen - D13S1226 - D13S260 - BRCA2 BRCA2 - D13S171 - D13S1493 - qter
    Physical map
    UBL3 13q12-q13 ubiquitin-like 3 MGC2599 13q12.3 hypothetical protein MGC2599 similar to katanin p60 subunit A 1 2599 PRDX2P1 13p12 peroxiredoxin 2 pseudogene 1 UBCH7N2 13q12.3 ubiquitin-conjugating enzyme-like HMGB1 13q12 high-mobility group box 1 LOC390392 13 similar to Protein-tyrosine phosphatase, non-receptor type 2 (T-cell protein-tyrosine phosphatase) (TCPTP) D13S106E 13q12-q14 highly charged protein ALOX5AP 13q12 arachidonate 5-lipoxygenase-activating protein LOC387917 13 LOC387917 FLJ14834 13q12.3 hypothetical protein FLJ14834 MGC40178 13q12.3 hypothetical protein MGC40178 HSPH1 13q12.3 heat shock 105kDa/110kDa protein 1 B3GTL 13q12.3 beta 3-glycosyltransferase-like GREAT 13q12.3 beta 3-glycosyltransferase-like LOC196549 13q12.3 similar to hypothetical protein FLJ20897 13CDNA73 13q12.3 hypothetical protein CG003 BRCA2 13q12.3 breast cancer 2, early onset IFIT1P 13q12-q13 interferon-induced protein with tetratricopeptide repeats 1, pseudogene CG018 13q12-q13 hypothetical gene CG018 PRO0297 13q12-q13 hypothetical gene CG018 LOC88523 13q12.3 CG016 CG005 APRIN 13q12.3 androgen-induced proliferation inhibitor LOC122038 13q13.1 similar to Mitochondrial import receptor subunit TOM22 homolog (Translocase of outer membrane 22 kDa subunit homolog) (hTom22) (1C9-2) KL 13q12 klotho LOC387918 13 LOC387918 STARD13 13q12-q13 START domain containing 13 RFC3 13q12.3-q13 replication factor C (activator 1) 3, 38kDa
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    27 - 11386 384.2 3418 - 2008 18990703
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticthymus   highly
    Digestivestomach   lowly
    Endocrinepancreas   lowly
    Lymphoid/Immunespleen   moderately
    Reproductivefemale systembreast  highly
     female systemovary  highly
     female systemplacenta  highly
     male systemtestis  highly
    Respiratorylung   highly
    Urinarykidney   moderately
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/Immunelymphocyte
    cell lineage
    cell lines breast cancer cell line (MCF7)
    fluid/secretion
    at STAGE
    cell cycle     cell cycle, interphase, S
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal PALB2 (partner and localizer of BRCA2)-binding domain
  • eight internal repeats (BRC 1-8 domains), with histone acetyltransferase intrinsic activity (HAT) which map to the N terminal region (truncated BRCA2 mutants are cytoplasmic and non functional), mediate the interaction of BRCA2 with RAD51, and essential for homology-directed repair (HDR) , and, Valine 1532 of BRC repeat 4 plays an important role in the interaction between BRCA2 and RAD51
  • a specific DMC1 interacting region in B2-6.5, (BRCA2 2340-2472)
  • two C terminal nuclear localization signals (NLS)
  • for binding ssDNA and dsDNA
  • a functional nuclear export sequence (NES1)(disruption of the NES function results in deregulation of BRCA2 export, which ultimately leads to centrosome disorder)
  • C-terminal DNA-binding domain (DBD), with unique structural features and C-terminal domain of BRCA2 (BRCA2CTD) interacted with TP53 TAD1 and TAD2, and including C-terminal RAD51 interaction domain (CTRD)
  • conjugated PhosphoP
    HOMOLOGY
    interspecies ortholog to Brca2, Mus musculus
    ortholog to brca2, Danio rerio
    ortholog to BRCA2, Pan troglodytes
    ortholog to Brca2, Rattus norvegicus
    ortholog to BRC-2, C-Elegans
    intraspecies homolog to RAD51 and RAD52 for cell cycle control and DNA repair through homologous recombination
    Homologene
    FAMILY
    CATEGORY tumor suppressor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus,nucleoplasm
    text
  • localizes to the centrosomes during the S and early M phases of the cell cycle
  • localizes to centrosomes as well as nuclei
  • localizes to centrosomes between G1 and prophase and is removed from the centrosomes during mitosis
  • downregulation of WTIP abolished BRCA2 centrosome localization and abnormal cell division
  • basic FUNCTION
  • histone acetyltransferase intrinsic activity (HAT)
  • involved in cell cycle control and in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair
  • is required for cellular proliferation during embryogenesis
  • involved in transcription-associated recombination (TAR)
  • playing an early role in homologous double-strand breaks repair pathway choice
  • involved in embryonic cellular proliferation
  • universal regulator of RAD51/DMC1 recombinase actions
  • as in mitotic cells, it is likely that BRCA2 may participate in nucleoprotein filament formation leading to subsequent repair
  • essential for the ability to survive DNA damage and efficient homology-directed repair, presumably in conjunction with the RAD51 recombinase
  • regulates both the intracellular localization and DNA-binding ability of RAD51
  • promotes homologous recombination comprising one major pathway of DNA double-strand break repair
  • may regulate the fidelity of late stages in cytokinesis and may have a role in normal organization of myosin II in the contractile ring during cell division
  • has a role in the cellular response to blocked DNA replication
  • a central role in recombination, assembling onto single-stranded DNA (ssDNA) as a nucleoprotein filament and catalysing the invasion and exchange of homologous DNA sequences
  • plays significant roles in DNA double-strand break repair
  • the BRC repeats of BRCA2 regulate DNA-binding selectivity by modulating RAD51-DNA interaction
  • may limit the metastatic potential of neoplastic cells by down-regulating MMP9 production through inhibition of PI3-kinase/AKT and activation of MAPK/ERK, effectively hindering cancer cell migration and invasion
  • plays an essential role in the chromatin assembly of RAD51 during homologous recombination repair (HRR)
  • PALB2 can work in concert with a BRCA2 construct to further promote D-loop formation
  • may act as a molecular chaperone for RAD51 loading
  • key mediator of homologous recombination
  • augments the functions of RAD51 that are essential for recombinational repair of DNA breaks
  • associates with telomeres during the S and G2 phases of the cell cycle and facilitates the loading of RAD51 onto telomeres
  • besides its role in DNA damage repair, also plays an important role in cytokinesis, transcription regulation, and cancer cell proliferation
  • prevents rather than repairs nucleolytic lesions at stalled replication forks to maintain genomic integrity and hence likely suppresses tumorigenesis through this replication-specific function
  • critical role for BRCA2 in maintaining genomic stability, and likely suppressing tumorigenesis, independent of homology-directed repair
  • HDR-independent role of BRCA2 in preventing the degradation of stalled replication forks and the resultant chromosome rearrangements has important implications for therapy
  • BRCA2 and PALB2 are main regulators of G2 checkpoint maintenance following DNA-damage
  • cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling its localization
  • cellular levels of BRCA2 and RAD51 are mutually dependent on each other, and that low levels of these proteins provide selective pressure for reduction of TP53, which permits cell growth
  • R-loops are frequently formed in cells and BRCA2 is required for their processing
  • has a key role in the repair of DNA double-strand breaks and interstrand cross-links by RAD51-mediated homologous recombination
  • has dual functionality promoting not only DNA repair but also preventing DNA lesions at stalled forks
  • by targeting RPA1 and mimicking DNA, SHFM1 functions with BRCA2 in a two-component homologous recombination mediator complex in genome maintenance and tumor suppression
  • likely unique and specialized functions for the BRC motifs of BRCA2 in promoting homologous recombination in meiotic and mitotic cells
  • multifunctional tumor suppressor involved in homologous recombination (HR), mitotic checkpoint regulation, and telomere homeostasis
  • CELLULAR PROCESS cell cycle
    nucleotide, repair, recombination
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    chromosome instability pathway
    a component
  • complex consisting of BRCA2, NPM, and ROCK2 maintains the numerical integrity of centrosomes and accurate cell division and dysfunction of this regulation might be involved in the tumorigenesis of breast cancer
  • INTERACTION
    DNA single- or double-stranded DNA
    RNA
    small molecule
    protein
  • BRCA1
  • BARD1
  • SHFM1
  • RAD52
  • DSS1
  • FANCG
  • the highly conserved C-terminal site in BRCA2 bound to FANCD2
  • meiosis-specific recombinase DMC1
  • RAD51, BCCIP and BRAF35 that are critical for meiotic and mitotic recombination, DNA double-strand break (DSB) repair, and chromosome segregation
  • PALB2, molecular scaffold in the formation of BRCA1-PALB2-BRCA2 complex for homologous recombination repair
  • interacts with plectin (interaction playing an important role in the regulation of centrosome localization and displacement of the centrosome may result in genomic instability and cancer development)
  • physical association between TP53 and BRCA2 may also have important implications in the control of homologous recombination
  • interactions with RAD51 and DMC1 are required for the localization of both proteins to nuclear foci that mark sites of DNA breakage
  • binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA)
  • binding of BRCA2 to ROCK2, an effector of Rho small GTPase
  • interaction with HMG20B, a protein of uncertain function containing a promiscuous DNA-binding domain and kinesin-like coiled coils, has been implicated in the G2-M transition
  • interacts with RAD51 through both the BRC repeats and the C-ter
  • specifically binds to RAD51 via eight BRC repeat motifs and delivers RAD51 to double-stranded DNA breaks
  • a BRCA2 fusion peptide deleted for the DNA binding domain and active in homologous recombination (HR) is completely dependent on interaction with the PALB2 tumor suppressor for activity
  • BRCA2 localization to the midbody by FLNA regulates CEP55 signaling and completion of cytokinesis
  • rigorous TP53-mediated regulation on RAD51 functions in HR even in the presence of BRCA2
  • MMP14 proteolysis of BRCA2 regulates the abundance of BRCA2 on centrosomes
  • BRCA2, a key RAD51 binding partner, coordinates the activity of the central cell-cycle drivers CDKs and PLK1 to promote RAD51-mediated genome stability control
  • BRCA2 repair factor, which binds to SHFM1, also associates with PCID2 in the cell
  • facilitates nucleation of RAD51 filaments at multiple sites on single-stranded DNA
  • FANCD2, BRIP1 and BRCA2 cooperate to promote replication fork recovery independently of the Fanconi Anemia core complex
  • FBN1, acts at the downstream of AURKA and BRCA2, promotes ovarian cancer metastasis through the TP53 and SNAI2-associated signaling
  • in response to replication stress, BRCA2 recruits RAD51 onto nascent DNA at stalled forks, protecting nascent DNA from nucleolitic cleavage
  • BABAM1 cooperates with BRCA2 to resolve DNA interstrand cross-links
  • ERCC5 is a partner of BRCA1 and BRCA2 in maintaining genomic stability through homologous recombination (HRR)
  • BRCA2 interacts directly with both RAD51 and DMC1 (pMID: 26976601)
  • WTIP interacts with BRCA2 and might be responsible for BRCA2 centrosome localization in cervical cancer cell
  • BRCA1 (FANCS), MDC1, and RNF8 are required for BRCA2 (FANCD1) and SLX4 (FANCP) accumulation on the sex chromosomes during meiosis
  • cell & other
    REGULATION
    Phosphorylated by CDK2 (phosphorylation of the BRCA2 C-terminal RAD51 binding site by CDK2 promotes RAD51 filament disassembly, leading to nucleolitic cleavage of newly synthesized DNA and compromised fork integrity)
    Other phosphorylation of S3291 is low in S phase when recombination is active, but increases as cells progress towards mitosis with inhibition of interactions with RAD51
    activated by PARP1 (appears to play a critical role in the regulation of BRCA2 transcription
    ASSOCIATED DISORDERS
    corresponding disease(s) BRCA2 , FANCB2 , FANCD1
    related resource Breastcancer
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral somatic mutation      
    in pancreatic, ovarian and stomach cancer
    tumoral somatic mutation     loss of function
    in breast and ovary carcinoma
    constitutional germinal mutation      
    rare germline mutations with prostate cancer susceptibility
    tumoral     --low  
    is lost in prostate carcinoma cells compared to normal and hyperplastic prostate epithelium
    tumoral     --low  
    BRCA2-deficient cells are likely particularly vulnerable to oncogene activation for the generation of chromosome aberrations leading to tumorigenesis
    tumoral germinal mutation     loss of function
    in patients with primary ovarian, fallopian tube, or peritoneal cancers
    Susceptibility
  • susceptibility gene for male breast cancer and abortion
  • predisposition to solid tumors in early childhood
  • to breast cancer
  • Variant & Polymorphism SNP
  • N372H increased risk in HH homozygotes
  • biallelic mutation associated with an increased risk of solid tumors in early childhood
  • variants R2108H, F2406L, L2653P, S2695L, I2944F, E3002K, D3095E, N3124I, increase risk of breast cancer
  • Candidate gene for a B-cell CLL tumor suppressor gene locus in 13q12.3
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Nullizygous BRCA2 embryos became developmentally retarded and disorganized, and died early in development
  • Brca2-deficient mice exhibited dysfunction of the spindle assembly checkpoint, accompanied by mutations in the p53, Bub1 and Mad3L genes
  • absence of Brca2 in mice results in progressive shortening of telomeres and senescence, yet cells are prone to neoplastic transformation with elongated telomeres, suggesting that Brca2 has positive and negative effects on telomere length regulation along the path to tumorigenesis