BRCA1 - Wikipedia, the free encyclopedia

Breast cancer 1, early onsetIdentifiersSymbolsExternal IDsRNA expression patternOrthologsSpeciesEntrezEnsemblUniProtRefSeq (mRNA)RefSeq (protein)Location (UCSC)PubMed search
PDB rendering based on 1jm7.
Available structuresPDB
Ortholog search: PDBe, RCSB
List of PDB id codes

1JM7, 1JNX, 1N5O, 1OQA, 1T15, 1T29, 1T2U, 1T2V, 1Y98, 2ING, 3COJ, 3K0H, 3K0K, 3K15, 3K16, 3PXA, 3PXB, 3PXC, 3PXD, 3PXE

BRCA1; BRCAI; BRCC1; BROVCA1; IRIS; PNCA4; PPP1R53; PSCP; RNF53
OMIM113705MGI104537HomoloGene5276ChEMBL: 5990GeneCards: BRCA1 Gene
More reference expression data
HumanMouse
67212189
ENSG00000012048ENSMUSG00000017146
P38398P48754
NM_007294NM_009764
NP_009225NP_033894
Chr 17:41.2 – 41.32 MbChr 11:101.49 – 101.55 Mb
[1][2]

BRCA1 (pron.:/ˈbrækə/;[1]breast cancer 1, early onset) is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA.[2] The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990.[3] Four years later, after an international race to find it,[4] the gene was cloned in 1994 by scientists at University of Utah, National Institute of Environmental Health Sciences (NIEHS) and Myriad Genetics.[5][6]

BRCA1 is expressed in the cells of breast and other tissue, where it helps repair damaged DNA, or destroy cells if DNA cannot be repaired. If BRCA1 itself is damaged, damaged DNA is not repaired properly and this increases risks for cancers (see BRCA mutation).[7][8]

The protein encoded by the BRCA1 gene combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC).[9] The BRCA1 protein associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. Thus, this protein plays a role in transcription, DNA repair of double-stranded breaks[8]ubiquitination, transcriptional regulation as well as other functions.[10]

Methods to diagnose the likelihood of a patient with mutations in BRCA1 and BRCA2 getting cancer were covered by patents owned or controlled by Myriad Genetics.[5][11] Myriad's business model of exclusively offering the diagnostic test led from Myriad being a startup in 1994 to being a publicly traded company with 1200 employees and about $500M in annual revenue in 2012;[12] it also led to controversy over high prices and the inability to get second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v. Myriad Genetics lawsuit.[13]

Gene location[edit]

The human BRCA1 gene is located on the long (q) arm of chromosome 17 at region 2 band 1, from base pair 41,196,312 to base pair 41,277,500 (Build GRCh37/hg19) (map).[14]BRCA1orthologs[15] have been identified in most mammals for which complete genome data are available.

Protein structure[edit]

The BRCA1 protein contains the following domains:[16]

This protein also contains nuclear localization signal and nuclear export signal motifs.[17]

The human BRCA1 protein consists of four major protein domains; the Znf C3HC4- RING domain, the BRCA1 serine domain and two BRCT domains. These domains encode approximately 27% of BRCA1 protein. There are six known isoforms of P38398 BRCA1, with isoforms 1 and 2 comprising 1863 amino acids each.

Zinc ring finger domain[edit]

The RING motif, a Zn finger found in eukaryotic peptides, is 40-60 amino acids long and consists of eight conserved metal-binding residues, two quartets of cysteine or histidine residues that coordinate two zinc atoms.[19] This motif contains a short anti-parallel beta-sheet, two zinc binding loops and a central alpha helix in a small domain. This RING domain interacts with associated proteins including BARD1, which also contains a RING motif, to form a heterodimer. The BRCA1 RING motif is flanked by alpha helices formed by residues 8-22 and 81-96 of the BRCA1 protein. It interacts with a homologous region in BARD1 also consisting of a RING finger flanked by two alpha-helices formed from residues 36-48 and 101-116. These four helices combine to form a heterodimerization interface and stabilise the BRCA1-BARD1 heterodimer complex. Additional stabilisation is achieved by interactions between adjacent residues in the flanking region and hydrophobic interactions. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression.[19]

The ring domain is an important element of ubiquitin E3 ligases which catalyse protein ubiquitination2. Ubiquitin is a small regulatory protein found in all tissues which directs proteins to compartments within the cell. BRCA1 polypeptides, in particular Lys-48-linked polyubiquitin chains, are dispersed throughout within the resting cell nucleus but when DNA replication begins they gather in restrained groups that also contain BRCA2 and BARD1. BARD1 is thought to be involved in the recognition and binding of protein targets for ubiquitination.[20] It attaches to proteins and labels them for destruction. Ubiquitination occurs via the BRCA1 fusion protein and is abolished by zinc chelation.[19] The enzyme activity of the fusion protein is dependent on the proper folding of the ring domain.

Serine cluster domain[edit]

The BRCA1 serine cluster domain (SCD) spans amino acids 1280-1524. A portion of the domain is located in exons 11-13. High rates of mutation occur in exons 11-13. Reported phosphorylation sites of BRCA1 are concentrated in the SCD where they are phosphorylated by ATM/ATR kinases both in vitro and in vivo. ATM/ATR are kinases activated by DNA damage. Mutation of serine residues may affect localization of BRCA1 to sites of DNA damage and DNA damage response function.[18]

BRCT domains[edit]

The dual repeat BRCT domain of the BRCA1 protein is an elongated structure approximately 70 Å long and 30-35 Å wide.[21] The 85-95 amino acid domains in BRCT can be found as single modules or as multiple tandem repeats containing two domains.[22] Both of these possibilities can occur in a single protein in a variety of different conformations.[21] The C-terminal BRCT region of the BRCA1 protein is essential for repair of DNA, transcription regulation and tumor suppressor function.[23] In BRCA1 the dual tandem repeatBRCT domains are arranged in a head-to-tail-fashion in the three-dimensional structure, burying 1600Å of hydrophobic, solvent accessible surface area in the interface. These all contribute to the tightly packed knob-in-hole structure that comprises the interface. These homologous domains interact to control cellular responses to DNA damage. It is therefore no surprise, that a missense mutation at the interface of these two proteins can have devastating consequences on the cell cycle, resulting in protein dysfunction and a greater risk of developing cancer. The linker that joins these two homologs also needs to be considered, since its poorly defined electron density alludes to a possible complex function; the ability to flex.[21]

Function and mechanism[edit]

BRCA1 repairs double-strand breaks in DNA. The strands of the DNA double helix are continuously breaking from damage. Sometimes one strand is broken, and sometimes both strands are broken simultaneously. DNA cross linking agents are an important source of chromosome/DNA damage. Double strand breaks occur as intermediates after the cross links are removed. BRCA1 is part of a protein complex that repairs DNA when both strands are broken. When both strands are broken, it is difficult for the repair mechanism to "know" how to replace the correct DNA sequence, and there are multiple ways to attempt the repair. The double-stranded repair mechanism that BRCA1 participates in is homologous recombination, in which the repair proteins utilize homologous intact sequence from a sister chromatid, from a homologous chromosome, or from the same chromosome (depending on cell cycle phase) as a template.[24] This DNA repair takes place with the DNA in the cell nucleus, wrapped around the histone. Several proteins, including BRCA1, arrive at the histone-DNA complex for this repair. Regulatory aspect to BRCA1 nuclear ⁄ non-nuclear distribution was first shown by Dr Rao laboratory in 1997[25]

In the nucleus of many types of normal cells, the BRCA1 protein interacts with RAD51 during repair of DNA double-strand breaks.[26] These breaks can be caused by natural radiation or other exposures, but also occur when chromosomes exchange genetic material (homologous recombination, e.g., "crossing over" during meiosis). The BRCA2 protein, which has a function similar to that of BRCA1, also interacts with the RAD51 protein. By influencing DNA damage repair, these three proteins play a role in maintaining the stability of the human genome.

BRCA1 directly binds to DNA, with higher affinity for branched DNA structures. This ability to bind to DNA contributes to its ability to inhibit the nuclease activity of the MRN complex as well as the nuclease activity of Mre11 alone.[27] This may explain a role for BRCA1 to promote lower fidelity DNA repair by non-homologous end joining (NHEJ).[28] BRCA1 also colocalizes with γ-H2AX (histone H2AX phosphorylated on serine-139) in DNA double-strand break repair foci, indicating it may play a role in recruiting repair factors.[10][29]

Formaldehyde and acetaldehyde are common environmental sources of DNA cross links that often require repairs mediated by BRCA1 containing pathways.[30][31]

Transcription[edit]

BRCA1 was shown to co-purify with the human RNA Polymerase II holoenzyme in HeLa extracts, implying it is a component of the holoenzyme.[32] Later research, however, contradicted this assumption, instead showing that the predominant complex including BRCA1 in HeLa cells is a 2 megadalton complex containing SWI/SNF.[33] SWI/SNF is a chromatin remodeling complex. Artificial tethering of BRCA1 to chromatin was shown to decondense heterochromatin, though the SWI/SNF interacting domain was not necessary for this role.[29] BRCA1 interacts with the NELF-B (COBRA1) subunit of the NELF complex.[29]

Other roles[edit]

Research suggests that both the BRCA1 and BRCA2 proteins regulate the activity of other genes and play a critical role in embryo development. The BRCA1 protein probably interacts with many other proteins, including tumor suppressors and regulators of the cell division cycle.

Mutations and cancer risk[edit]

Certain variations of the BRCA1 gene lead to an increased risk for breast cancer as part of a hereditary breast-ovarian cancer syndrome. Researchers have identified hundreds of mutations in the BRCA1 gene, many of which are associated with an increased risk of cancer. Women with an abnormal BRCA1 or BRCA2 gene have up to a 80% risk of developing breast cancer by age 90; increased risk of developing ovarian cancer is about 55% for women with BRCA1 mutations and about 25% for women with BRCA2 mutations.[34]

These mutations can be changes in one or a small number of DNA base pairs (the building-blocks of DNA). Those mutations can be identified with PCR and DNA sequencing.

In some cases, large segments of DNA are rearranged. Those large segments, also called large rearrangements, can be a deletion or a duplication of one or several exons in the gene. Classical methods for mutations detection (sequencing) are unable to reveal those mutations.[35] Other methods are proposed: Q-PCR,[36]Multiplex Ligation-dependent Probe Amplification (MLPA),[37] and Quantitative Multiplex PCR of Shorts Fluorescents Fragments (QMPSF).[38] New methods have been recently proposed: heteroduplex analysis (HDA) by multi-capillary electrophoresis or also dedicated oligonucleotides array based on comparative genomic hybridization (array-CGH).[39]

Some results suggest that hypermethylation of the BRCA1 promoter, which has been reported in some cancers, could be considered as an inactivating mechanism for BRCA1 expression.[40]

A mutated BRCA1 gene usually makes a protein that does not function properly because it is abnormally short. Researchers believe that the defective BRCA1 protein is unable to help fix mutations that occur in other genes. These defects accumulate and may allow cells to grow and divide uncontrollably to form a tumor.

BRCA1 mRNA 3' UTR can be bound by an miRNA, Mir-17 microRNA. It has been suggested that variations in this miRNA along with Mir-30 microRNA could confer susceptibility to breast cancer.[41]

In addition to breast cancer, mutations in the BRCA1 gene also increase the risk of ovarian, fallopian tube, and prostate cancers. Moreover, precancerous lesions (dysplasia) within the Fallopian tube have been linked to BRCA1 gene mutations. Pathogenic mutations anywhere in a model pathway containing BRCA1 and BRCA2 greatly increase risks for a subset of leukemias and lymphomas.[8]

Women having inherited a defective BRCA1 or BRCA2 gene have risks for breast and ovarian cancer that are so high and seem so selective that many mutation carriers choose to have prophylactic surgery. There has been much conjecture to explain such apparently striking tissue specificity. Major determinants of where BRCA1/2 hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen. The target tissue may have receptors for the pathogen, become selectively exposed to an inflammatory process or to a carcinogen. An innate genomic deficit in a tumor suppressor gene impairs normal responses and exacerbates the susceptibility to disease in organ targets. This theory also fits data for several tumor suppressors beyond BRCA1 or BRCA2. A major advantage of this model is that it suggests there may be some options in addition to prophylactic surgery.[citation needed]

Germ line mutations and founder effect[edit]

All germ-line BRCA1 mutations identified to date have been inherited, suggesting the possibility of a large “founder” effect in which a certain mutation is common to a well-defined population group and can, in theory, be traced back to a common ancestor. Given the complexity of mutation screening for BRCA1, these common mutations may simplify the methods required for mutation screening in certain populations. Analysis of mutations that occur with high frequency also permits the study of their clinical expression.[42] Examples of manifestations of a founder effect are seen among Ashkenazi Jews. Three mutations in BRCA1 have been reported to account for the majority of Ashkenazi Jewish patients with inherited BRCA1-related breast and/or ovarian cancer: 185delAG, 188del11 and 5382insC in the BRCA1 gene.[43][44] In fact, it has been shown that if a Jewish woman does not carry a BRCA1 185delAG, BRCA1 5382insC founder mutation, it is highly unlikely that a different BRCA1 mutation will be found.[45] Additional examples of founder mutations in BRCA1 are given in Table 1 (mainly derived from [42]).

Population or subgroupBRCA1 mutation(s)[46]Reference(s)
African-Americans943ins10, M1775R[47]
AfrikanersE881X[48]
Ashkenazi Jewish185delAG, 188del11, 5382insC[43][44]
Austrians2795delA, C61G, 5382insC, Q1806stop[49]
Belgians2804delAA, IVS5+3A>G[50][51]
DutchExon 2 deletion, exon 13 deletion, 2804delAA[50][52][53]
Finns3745delT, IVS11-2A>G[54][55]
French3600del11, G1710X[56]
French CanadiansC4446T[57]
Germans5382insC, 4184del4[58][59]
Greeks5382insC[60]
Hungarians300T>G, 5382insC, 185delAG[61]
Italians5083del19[62]
JapaneseL63X, Q934X[63]
Native North Americans1510insG, 1506A>G[64]
Northern Irish2800delAA[65]
Norwegians816delGT, 1135insA, 1675delA, 3347delAG[66][67]
Pakistanis2080insA, 3889delAG, 4184del4, 4284delAG, IVS14-1A>G[68]
Polish300T>G, 5382insC, C61G, 4153delA[69][70]
Russians5382insC, 4153delA[71]
Scottish2800delAA[65][72]
SpanishR71G[73][74]
SwedishQ563X, 3171ins5, 1201del11, 2594delC[47][75]

Patents, enforcement, litigation, and controversy[edit]

A patent application for the isolated BRCA1 gene and cancer-cancer promoting mutations discussed above, as well as methods to diagnose the likelihood of getting breast cancer, was filed by the University of Utah, National Institute of Environmental Health Sciences (NIEHS) and Myriad Genetics in 1994;[5] over the next year, Myriad, in collaboration with investigators at Endo Recherche, Inc., HSC Research & Development Limited Partnership, and University of Pennsylvania, isolated and sequenced the BRCA2 gene and identified key mutations, and the first BRCA2 patent was filed in the U.S. by Myriad and other institutions in 1995.[11] Myriad is the exclusive licensee of these patents and has enforced them in the US against clinical diagnostic labs.[13] This business model led from Myriad being a startup in 1994 to being a publicly traded company with 1200 employees and about $500M in annual revenue in 2012;[12] it also led to controversy over high prices and the inability to get second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v. Myriad Genetics lawsuit.[13][76] The patents begin to expire in 2014.

According to an article published in the journal, Genetic Medicine, in 2010, "The patent story outside the United States is more complicated.... For example, patents have been obtained but the patents are being ignored by provincial health systems in Canada. In Australia and the UK, Myriad’s licensee permitted use by health systems, but announced a change of plans in August 2008. ... Only a single mutation has been patented in Myriad’s lone European-wide patent, although some patents remain under review of an opposition proceeding. In effect, the United States is the only jurisdiction where Myriad’s strong patent position has conferred sole-provide status."[77][78] Peter Meldrum, CEO of Myriad Genetics, has acknowledged that Myriad has "other competitive advantages that may make such [patent] enforcement unnecessary" in Europe.[79]

Legal decisions surrounding the BRCA1 and BRCA2 patents will affect the field of genetic testing in general.[80]

Interactions[edit]

BRCA1 has been shown to interact with

Browser view[edit]

View a graphical representation of all GenBank isoforms at the UCSC Genome Browser

UCSC Gene details page

See also[edit]

References[edit]

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External links[edit]

PDB gallery

1jm7: Solution structure of the BRCA1/BARD1 RING-domain heterodimer 

1jnx: Crystal structure of the BRCT repeat region from the breast cancer associated protein, BRCA1 

1n5o: Structural consequences of a cancer-causing BRCA1-BRCT missense mutation 

1oqa: Solution structure of the BRCT-c domain from human BRCA1 

1t15: Crystal Structure of the Brca1 BRCT Domains in Complex with the Phosphorylated Interacting Region from Bach1 Helicase 

1t29: Crystal structure of the BRCA1 BRCT repeats bound to a phosphorylated BACH1 peptide 

1t2u: Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1: structure of BRCA1 missense variant V1809F 

1t2v: Structural basis of phospho-peptide recognition by the BRCT domain of BRCA1, structure with phosphopeptide 

1y98: Structure of the BRCT repeats of BRCA1 bound to a CtIP phosphopeptide. 

http://en.wikipedia.org/wiki/BRCA1