BRCA1 (; 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. It originally stood for Berkeley, California, as the first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990. The gene was later cloned in 1994 by scientists at Myriad Genetics.

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.

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). 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 ubiquitination, transcriptional regulation as well as other functions.

Gene location

The human BRCA1 gene is located on the long (q) arm of chromosome 17 at band 21, from base pair 38,429,551 to base pair 38,551,283 (Build GRCh37/hg19) (map). BRCA1 orthologs have been identified in most mammals for which complete genome data are available.

Protein structure

The BRCA1 protein (breast cancer type 1 susceptibility protein also known as RING finger protein 53) contains the following domains:

Zinc finger, C3HC4 type (RING finger)

BRCA1 C Terminus (BRCT) domain

This protein also contains nuclear localization signal and nuclear export signal motifs.

Function and mechanism

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. 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. 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

In the nucleus of many types of normal cells, the BRCA1 protein interacts with RAD51 during repair of DNA double-strand breaks. 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. This may explain a role for BRCA1 to promote higher fidelity DNA repair by non-homologous end joining (NHEJ). 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.

Transcription

BRCA1 was shown to co-purify with the human RNA Polymerase II holoenzyme in HeLa extracts, implying it is a component of the holoenzyme. 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. 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. BRCA1 interacts with the NELF-B (COBRA1) subunit of the NELF complex.

Other roles

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

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 60% 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.

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. Other methods are proposed: Q-PCR, Multiplex Ligation-dependent Probe Amplification (MLPA), and Quantitative Multiplex PCR of Shorts Fluorescents Fragments (QMPSF). 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).

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.

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.

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.

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.

Germ line mutations and founder effect

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. 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. 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. Additional examples of founder mutations in BRCA1 are given in Table 1 (mainly derived from ).

{| class="wikitable" |- ! Population or subgroup !! BRCA1 mutation(s) !! Reference(s) |- | African-Americans || 943ins10, M1775R || |- | Ashkenazi Jewish || 185delAG, 188del11, 5382insC || |- | Austrians || 2795delA, C61G, 5382insC, Q1806stop || |- | Belgians || 2804delAA, IVS5+3A>G || |- | Dutch || Exon 2 deletion, exon 13 deletion, 2804delAA || |- | Finns || 3745delT, IVS11-2A>G || |- | French || 3600del11, G1710X || |- | French Canadians || C4446T || |- | Germans || 5382insC || 4184del4 Ref. http://mutview.dmb.med.keio.ac.jp/MutationView/jsp/mutview/html/brca1.html |- | Greeks || 5382insC || |- | Hungarians || 300T>G, 5382insC, 185delAG || |- | Italians || 5083del19 || |- | Japanese || L63X, Q934X || |- | Native North Americans || 1510insG, 1506A>G || |- | Northern Irish || 2800delAA || |- | Norwegians || 816delGT, 1135insA, 1675delA, 3347delAG || |- | Pakistanis || 2080insA, 3889delAG, 4184del4, 4284delAG, IVS14-1A>G || |- | Polish || 300T>G, 5382insC, C61G, 4153delA || |- | Russians || 5382insC, 4153delA || |- | Scottish || 2800delAA || |- | South Africans || E881X || |- | Spanish || R71G || |- | Swedish || Q563X, 3171ins5, 1201del11, 2594delC || |}

Patent

Methods to isolate and detect BRCA1 and BRCA2 were patented in the United States by Myriad Genetics. This US patent has been challenged by the American Civil Liberties Union. On March 29, 2010, a coalition led by the American Civil Liberties Union (ACLU) successfully challenged the basis of Myriad’s patents in New York District Court. The patent was invalidated, but the decision was appealed. On July 29th 2011 the United States Court of Appeals for the Federal Circuit made their decision and ruled that Myriads patents are valid.

Interactions

BRCA1 has been shown to interact with ABL1, AKT1, AR, ATR, ATM, ATF1, AURKA, BACH1, BARD1, BRCA2, BRCC3, BRE, BRIP1, C-jun, CHEK2, CLSPN, COBRA1, CREBBP, CSNK2B, CSTF2, CDK2, DHX9, ELK4, EP300, ESR1, FANCA, FANCD2, FHL2, H2AFX, JUNB, JunD, LMO4, MAP3K3, MED1, MED17, MED21, MED24, MRE11A, MSH2, MSH3, MSH6, Myc, NBN, NMI, NPM1, NCOA2, NUFIP1, P53, PALB2, POLR2A, PPP1CA, Rad50, RAD51, RBBP4, RBBP7, RBBP8, RELA, RB1, RBL1, RBL2, RPL31, SMARCA4 SMARCB1, STAT1, UBE2D1, USF2, VCP, XIST, and ZNF350,

Browser view

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

UCSC Gene details page

See also

BRCA2

Breast cancer

Mary-Claire King

References

Further reading

External links

GeneReviews/NCBI/NIH/UW entry on BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer

OMIM entries on BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer

Category:Genes on chromosome 17 Category:Tumor markers Category:Tumor suppressor genes

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