BRCA1 (breast cancer 1, early onset)

2007-10-01   Sreeparna Banerjee 

Department of Biology, Office: Z-16\\\/Lab: B-59, Middle East Technical University, 06531 Ankara, Turkey





The subcellular localization and physiological function of this gene is greatly modulated by the several alternately splices isoforms that are found. Several of these alternatively spliced transcript variants have been described, however, not all have had their full-length natures identified.


According to Entrez-Gene, BRCA1 gene maps to NC_000017.9 in the region between 38449840 and 38530994 on the minus strand and spans across 81.1 kilo bases. According to Spidey (mRNA to genomic sequence alignment tool,, BRCA1 has 24 exons, the sizes being 181, 99, 54, 78, 89, 140, 105, 47, 77, 89, 172, 127, 191, 311, 88, 78, 41, 84, 55, 74, 61, 1506.


BRCA1 mRNA NM_007302.3 has 7388bps. The BRCA1 gene contains two separate promoters that induce transcription of mRNAs with different 5 UTRs, a shorter 5UTRa and a longer 5UTRb. The downregulation of BRCA1 gene expression in certain breast cancers is caused by a switch from expression of a 5UTRa, which enables efficient translation, to expression of 5 UTRb, which contains secondary structure and upstream open reading frames that strongly inhibit translation.


According to Entrez Gene the BRCA1 pseudogene 1 (BRCA1P1) is located on 17q21.



BRCA1 sequence is not well conserved between mammals, however, two domains, the C terminal BRCT (BRCA1 C Terminal) motifs and the N-terminal RING domain are highly conserved.
Atlas Image
The BRCA1 protein showing the RING finger domain, the Nuclear Localisation Signal domain and the BRCT domains. AA- amino acids.


BRCA1 is an 1863 amino acid 220kDa protein with an E3 ubiquitin ligase activity as well as a phospho-peptide binding activity. It has several domains that are essential for its function as depicted in the figure. The RING finger domain of BRCA1, commonly found in many DNA repair proteins, consists of a conserved core of approximately 50 amino acids in a pattern of seven cysteine residues and one histidine residue to form a structure that can bind to two Zn++ ions. This motif aids in mediating protein-protein interaction, as exemplified by the interaction of BRCA1 with BARD1 (BRCA1 associated RING domain). This interaction is critical since mutations in the Zn++ binding regions, crucial for heterodimerization with BARD1, have been found in tumours. BRCA1 accumulates in distinct foci in the nucleus during S phase and this transfer is aided by its Nuclear Localisation Signal (NLS) domain. A further role of BARD1 is also implicated whereby its association with the RING finger domain of BRCA1 is necessary for the transfer of BRCA1 to the nucleus. BRCA1 interacts with Rad50 of the MRN complex through the region AA 341-748 and can directly bind to branched, flap and four way DNA structures through a central domain spanning residues 452-1079. The protein inhibits the nucleolytic activities of the Mre11/Rad50/Nbs1 complex as a result of this direct DNA binding. The C terminus of BRCA1, which can function as a transcriptional activation domain, consists of two tandemly arranged elements called BRCT (BRCA1 C- terminal). This motif specifically binds to phosphorylated proteins, an event that is commonly associated with DNA damage response. BRCA1 is capable of interacting directly with BRCA2 and with Rad51 via BRCA2 through this motif. Another protein that interacts with BRCA1 via BRCT is the BRCA1 associated C-terminal helicase ( BACH1 ). BACH1 is said to aid BRCA1 in the DNA damage response and maintain the protein at the nuclear foci formed after DNA damage response. Other proteins that can interact with BRCA1 through the BRCT domains are C terminal Interacting protein /CtIP), RNA Polymerase II, BACH 1 (a member of DEAH helicase family) and p53 .


BRCA1 is ubiquitously expressed in humans with the highest levels observed in the ovaries, testis and thymus. It is a tumour suppressor and a reduced expression is correlated with the transformation procedure and aetiology of sporadic breast cancer. This reduction is expression is said to be transcriptionally regulated with implications of aberrant promoter methylation at CpG dinucleotides as well as CREB binding sites.


Located in the nucleus.


Role of BRCA1 in DNA repair: BRCA1 is a part of a large complex of proteins, the BASC, which monitors the genome for damage and signals downstream effectors. BRCA1 has been implicated in two pathways of DNA double strand break repair: homologous recombination (HR) and non homologous end joining (NHEJ). Upon exposure to DNA damaging agents, BRCA1 becomes hyperphosphorylated and is rapidly relocated, along with Rad51, to sites of DNA synthesis marked by proliferating cell nuclear antigen (PCNA). Rad51, a homolog of the bacterial RecA, is a central player in HR, catalyzing the invasion of the single stranded DNA in a homologous duplex and facilitating the homology search during the establishment of joint molecules. A recent study, however, has indicated that BRCA1 deficient breast cancer cells compensate for this deficiency by upregulating Rad51. The resultant HR may be erroneous and thereby lead to tumorigenesis. In addition, BRCA1 is said to inhibit the MRN complex which is is implicated in bringing together two DNA strands together for the error prone NHEJ. BRCA1-deficient cells are sensitive to ionizing radiation and DNA damaging drugs, such as mitomycin C.
Transcriptional regulation: BRCA1 is capable of transcriptional regulation and chromatin remodelling when tethered to promoters of genes important in the DNA repair process and breast cancer markers. It is a member of the core RNA polymerase II transcriptional machinery, a feature exploited by the DNA damage recognition process. In addition, BRCA1 interacts with p300/CBP, transcriptional coactivators for CREB. p300/CBP are inhibited by the viral oncoprotein E1A and the functionality of E1A as an oncogene could be in part caused by an obstruction of BRCA1:p300/CBP cooperation resulting in the loss of the tumour-suppressing function of BRCA1. BRCA1 can act as a transcriptional coactivator or co repressor of proteins implicated in chromatin remodelling, such as the histone deacetylase complexes or components of the SWI/SNF-related chromatin-remodelling complex.
Cell Cycle Regulation by BRCA1: BRCA1, based on its phosphorylation status, elicits DNA damage induced cell cycle arrest at several stages through modulation of specific downstream target genes. BRCA1 transactivates p21cip1/WAF1, which contributes to an arrest at the G1/S boundary. ATM phosphorylation of BRCA1 appears to be important for its role in the intra S phase checkpoint activation. BRCA1 is also implicated in the transcriptional regulation of several genes such as cyclinB, 14-3-3sigma, GADD45, wee-1 kinase and PLK1 associated with the G2/M checkpoint.
p53-dependent apoptosis: The BRCA1 protein is capable of physically interacting with the p53 tumour suppressor gene, and can stimulate p53-dependent transcription from the p21WAF1/CIP1 mdm2 and promoters. In addition, the BRCA1-BARD1 complex is required for the phosphorylation of p53 at Ser15 by ATM/ATR following DNA damage by IR or UV radiation. The phosphorylation of p53 at Ser-15 is essential for the G(1)/S cell cycle arrest via transcriptional induction of the cyclin-dependent kinase inhibitor p21 after DNA damage.
Ubiquitination: BRCA1 and BARD1 interact together to form an E3 ubiquitin ligase. RNA polII stalled at sites of DNA damage is a target for this ubiquitin ligase mediated degradation following DNA damage, thereby allowing access to the repair machinery. BRCA1 ubiquitinates the transcriptional preinitiation complex, not for proteasomal degradation, but to prevent a stable association of TFIIE and TFIIH; thereby blocking the initiation of mRNA synthesis.


Dog (Canis familiaris): BRCA1
Chimpanzee(Pan troglodytes): BRCA1
Rat (Rattus norvegicus): Brca1
Mouse(Mus musculus): Brca1
Chicken(Gallus gallus): BRCA1



BRCA1 germline mutations contribute significantly to the development of familial/hereditary breast and ovarian cancer. However, each gene carries as many as 1000 different disease associated mutations, many of which are rare. These mutations are distributed uniformly along the entire coding region and intronic sequences flanking each exon. The mutations are at a high penetrance therefore women who carry these mutations have a lifetime risk of 80-90% to develop breast cancer. Founder mutations such as the BRCA1-185delAG and 5382insC are found among Ashkenazi Jews. Larger and complex genomic rearrangements in the exons 21 and 22 of the BRCA1 gene, resulting in a lack of the BRCT motif have been reported.

Implicated in

Entity name
Breast Cancer
Heterozygous carriers of high-risk mutations in the general Caucasian population have been estimated to be about one in 1000 for the BRCA1 gene. The lifetime risk of the development of hereditary breast cancer with the presence of BRCA1 mutations is very high. In addition, for sporadic breast cancer, a reduction in the expression of BRCA1 rather than the presence of mutations has been observed. The lack of a functional BRCA1 leads to impaired repair of DNA double strand breaks, cell cycle progression and transcriptional regulation, thereby causing the development of neoplasms.
Entity name
Ovarian Cancer
Mutations of the BRCA1 gene is the major cause for familial breast and ovarian cancer incidence. The lifetime risks of ovarian cancer associated with a BRCA1 gene mutation carrier has been estimated as 40 to 50%. The most common mutations are frameshift and nonsense mutations that are predicted to cause premature truncation of the BRCA1 protein. In addition, mutations that are predicted to affect splice-site consensus sequences as well as missense mutation have also been seen in ovarian cancer. Large genomic alterations, such as the gains in copy number of exon 13 as well as deletion of exons in the BRCA1 gene is also associated with the development of ovarian cancer.
Entity name
Other cancers
An increased relative risk to the development of cancer of the colon, cervix, uterus, pancreas and prostate has been suggested in BRCA1-mutation carriers.


Pubmed IDLast YearTitleAuthors
117048362001A CREB site in the BRCA1 proximal promoter acts as a constitutive transcriptional element.Atlas E et al
89295431996Human Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro.Baumann P et al
170521682006Cellular functions of the BRCA tumour-suppressor proteins.Boulton SJ et al
163575292006Assessing the link between BACH1 and BRCA1 in the FA pathway.Cantor SB et al
99269421999The second BRCT domain of BRCA1 proteins interacts with p53 and stimulates transcription from the p21WAF1/CIP1 promoter.Chai YL et al
87514361996Transcriptional activation by BRCA1.Chapman MS et al
97749701998Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells.Chen J et al
161037512005Good timing in the cell cycle for precise DNA repair by BRCA1.Durant ST et al
119254362002BARD1 induces BRCA1 intranuclear foci formation by increasing RING-dependent BRCA1 nuclear import and inhibiting BRCA1 nuclear export.Fabbro M et al
151593972004BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage.Fabbro M et al
175918432007Founder mutations in BRCA1 and BRCA2 genes.Ferla R et al
112782472001The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation.Hashizume R et al
174204712007A mechanism for transcriptional repression dependent on the BRCA1 E3 ubiquitin ligase.Horwitz AA et al
124835142002Homologous repair of DNA damage and tumorigenesis: the BRCA connection.Jasin M et al
179428952007RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors.Martin RW et al
75459541994A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.Miki Y et al
169985002006The role of BRCA1 in transcriptional regulation and cell cycle control.Mullan PB et al
174989662007Genetic susceptibility for breast cancer: how many more genes to be found?Oldenburg RA et al
94828801998BRCA1 regulates p53-dependent gene expression.Ouchi T et al
106554772000CBP/p300 interact with and function as transcriptional coactivators of BRCA1.Pao GM et al
113538432001Direct DNA binding by Brca1.Paull TT et al
164627732006BACH1 is a DNA repair protein supporting BRCA1 damage response.Peng M et al
176882362007Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer.Ramus SJ et al
97780461998Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells.Rice JC et al
92070571997BRCA1 is a cell cycle-regulated nuclear phosphoprotein.Ruffner H et al
91591191997BRCA1 is a component of the RNA polymerase II holoenzyme.Scully R et al
92670231997Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage.Scully R et al
152806602004Molecular functions of BRCA1 in the DNA damage response.Scully R et al
118773862002Structural determinants of BRCA1 translational regulation.Sobczak K et al
165517092006Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer.Walsh T et al
107831652000BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.Wang Y et al
104269991999Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response.Zhong Q et al
178687472008Novel complex genomic rearrangement of the BRCA1 gene.Zikan M et al

Other Information

Locus ID:

NCBI: 672
MIM: 113705
HGNC: 1100
Ensembl: ENSG00000012048


dbSNP: 672
ClinVar: 672
TCGA: ENSG00000012048


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Homologous recombinationKEGGko03440
Ubiquitin mediated proteolysisKEGGko04120
Homologous recombinationKEGGhsa03440
Ubiquitin mediated proteolysisKEGGhsa04120
Fanconi anemia pathwayKEGGko03460
Fanconi anemia pathwayKEGGhsa03460
BRCA1-associated genome surveillance complex (BASC)KEGGhsa_M00295
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
BRCA1-associated genome surveillance complex (BASC)KEGGM00295
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
SUMO E3 ligases SUMOylate target proteinsREACTOMER-HSA-3108232
SUMOylation of DNA damage response and repair proteinsREACTOMER-HSA-3108214
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G2/M CheckpointsREACTOMER-HSA-69481
G2/M DNA damage checkpointREACTOMER-HSA-69473
Meiotic recombinationREACTOMER-HSA-912446
Meiotic synapsisREACTOMER-HSA-1221632
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
DNA Double Strand Break ResponseREACTOMER-HSA-5693606
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksREACTOMER-HSA-5693565
Homology Directed RepairREACTOMER-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
Processing of DNA double-strand break endsREACTOMER-HSA-5693607
HDR through Homologous Recombination (HRR)REACTOMER-HSA-5685942
Homologous DNA Pairing and Strand ExchangeREACTOMER-HSA-5693579
Presynaptic phase of homologous DNA pairing and strand exchangeREACTOMER-HSA-5693616
Resolution of D-Loop StructuresREACTOMER-HSA-5693537
Resolution of D-loop Structures through Holliday Junction IntermediatesREACTOMER-HSA-5693568
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)REACTOMER-HSA-5693554
HDR through Single Strand Annealing (SSA)REACTOMER-HSA-5685938
Nonhomologous End-Joining (NHEJ)REACTOMER-HSA-5693571
TP53 Regulates Transcription of DNA Repair GenesREACTOMER-HSA-6796648
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756
Platinum drug resistanceKEGGko01524
Platinum drug resistanceKEGGhsa01524
Metalloprotease DUBsREACTOMER-HSA-5689901
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA166158714[GRCh37]chr17:41276046VariantVipGeneassociated11896095, 7550349, 7606717, 7837387, 7894492, 8841191, 8898735, 9333265, 11466700
PA166158719[GRCh37]chr17:41209080VariantVipGeneassociated11896095, 7550349, 7837387, 7894492, 8841191, 8898735, 9333265, 11466700
PA443560Breast NeoplasmsDiseaseVipGeneassociated11034065, 11130383, 11896095, 12237281, 12237282, 15197194, 15254424, 16331614, 16445371, 16636335, 7545954, 7837387, 9145676, 9333265, 10208417
PA443685Uterine Cervical NeoplasmsDiseaseVipGeneassociated12237281
PA443756Colonic NeoplasmsDiseaseVipGeneassociated12237282
PA444144Fallopian Tube NeoplasmsDiseaseVipGeneassociated12237282
PA445062NeoplasmsDiseaseVipGeneassociated11034065, 11130383, 11896095, 12237281, 12237282, 15197194, 15254424, 16331614, 16636335, 7837387, 9145676, 9333265, 10208417
PA445204Ovarian NeoplasmsDiseaseVipGeneassociated11034065, 11130383, 11896095, 12237281, 12237282, 15197194, 15254424, 16331614, 16636335, 7545954, 7837387, 9145676, 9333265, 10208417
PA445218Pancreatic NeoplasmsDiseaseVipGeneassociated12237282, 12237281
PA445425Prostatic NeoplasmsDiseaseVipGeneassociated12237282, 9145676, 12237281
PA445742Stomach NeoplasmsDiseaseVipGeneassociated12237282
PA446004Uterine NeoplasmsDiseaseVipGeneassociated12237281
PA446745Breast Neoplasms, MaleDiseaseVipGeneassociated12237282, 11896095
PA451581tamoxifenChemicalVipGeneassociated15197194, 16331614, 16636335, 11130383


Pubmed IDYearTitleCitations
195536412009Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.1126
126775582003Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies.777
126775582003Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies.777
196489282009Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers.573
206094672010Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.564
145764342003Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.529
145764342003Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.529
206094682010Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.447
174168532007Meta-analysis of BRCA1 and BRCA2 penetrance.420
20453858201053BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers.385


Sreeparna Banerjee

BRCA1 (breast cancer 1, early onset)

Atlas Genet Cytogenet Oncol Haematol. 2007-10-01

Online version: