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The Info List - BRCA1


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1JM7, 1JNX, 1N5O, 1OQA, 1T15, 1T29, 1T2U, 1T2V, 1Y98, 2ING, 3COJ, 3K0H, 3K0K, 3K15, 3PXA, 3PXB, 3PXC, 3PXD, 3PXE, 4IFI, 4IGK, 4JLU, 4OFB, 4U4A, 4Y18, 4Y2G

Identifiers

Aliases BRCA1, breast cancer 1, early onset, BRCAI, BRCC1, BROVCA1, IRIS, PNCA4, PPP1R53, PSCP, RNF53, FANCS, breast cancer 1, DNA
DNA
repair associated

External IDs OMIM: 113705 MGI: 104537 HomoloGene: 5276 GeneCards: BRCA1

Gene
Gene
location (Human)

Chr. Chromosome
Chromosome
17 (human)[1]

Band 17q21.31 Start 43,044,295 bp[1]

End 43,170,245 bp[1]

Gene
Gene
location (Mouse)

Chr. Chromosome
Chromosome
11 (mouse)[2]

Band 11 65.18 cM11 D Start 101,488,764 bp[2]

End 101,551,955 bp[2]

RNA expression pattern

More reference expression data

Gene
Gene
ontology

Molecular function • tubulin binding • metal ion binding • enzyme binding • zinc ion binding • damaged DNA
DNA
binding • protein binding • transcription coactivator activity • androgen receptor binding • RNA binding • ubiquitin protein ligase binding • transcription regulatory region DNA
DNA
binding • ubiquitin-protein transferase activity • DNA
DNA
binding • transferase activity • RNA polymerase II
RNA polymerase II
transcription coactivator activity • RNA polymerase binding

Cellular component • BRCA1- BARD1
BARD1
complex • condensed nuclear chromosome • gamma-tubulin ring complex • BRCA1-A complex • ubiquitin ligase complex • plasma membrane • nucleoplasm • condensed chromosome • cytoplasm • chromosome • Cell nucleus • lateral element • macromolecular complex

Biological process • response to ionizing radiation • centrosome cycle • chromosome segregation • protein K6-linked ubiquitination • intrinsic apoptotic signaling pathway in response to DNA
DNA
damage • cell cycle • double-strand break repair via nonhomologous end joining • apoptotic process • regulation of apoptotic process • regulation of gene expression by genetic imprinting • regulation of transcription, DNA-templated • negative regulation of fatty acid biosynthetic process • transcription, DNA-templated • regulation of transcription from RNA polymerase III promoter • fatty acid biosynthetic process • regulation of DNA
DNA
methylation • negative regulation of intracellular estrogen receptor signaling pathway • protein autoubiquitination • positive regulation of histone H3-K9 methylation • DNA
DNA
recombination • positive regulation of angiogenesis • response to estrogen • cellular response to indole-3-methanol • negative regulation of extrinsic apoptotic signaling pathway via death domain receptors • negative regulation of transcription, DNA-templated • positive regulation of protein ubiquitination • androgen receptor signaling pathway • negative regulation of centriole replication • postreplication repair • lipid metabolic process • cellular response to tumor necrosis factor • positive regulation of DNA
DNA
repair • fatty acid metabolic process • positive regulation of gene expression • negative regulation of histone H3-K4 methylation • regulation of cell proliferation • negative regulation of reactive oxygen species metabolic process • positive regulation of vascular endothelial growth factor production • DNA
DNA
damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator • positive regulation of cell cycle arrest • positive regulation of transcription from RNA polymerase II promoter • positive regulation of histone H4-K20 methylation • DNA
DNA
double-strand break processing • strand displacement • double-strand break repair via homologous recombination • negative regulation of histone acetylation • regulation of signal transduction by p53 class mediator • protein ubiquitination • positive regulation of histone H3-K4 methylation • DNA
DNA
repair • DNA
DNA
synthesis involved in DNA
DNA
repair • double-strand break repair • positive regulation of histone acetylation • dosage compensation by inactivation of X chromosome • negative regulation of histone H3-K9 methylation • positive regulation of histone H3-K9 acetylation • positive regulation of transcription, DNA-templated • chordate embryonic development • positive regulation of histone H4-K16 acetylation • cellular response to DNA
DNA
damage stimulus • protein deubiquitination • DNA
DNA
replication • mitotic G2/M transition checkpoint • regulation of transcription from RNA polymerase II
RNA polymerase II
promoter • negative regulation of G0 to G1 transition • transcription from RNA polymerase II
RNA polymerase II
promoter • signal transduction involved in G2 DNA
DNA
damage checkpoint

Sources:Amigo / QuickGO

Orthologs

Species Human Mouse

Entrez

672

12189

Ensembl

ENSG00000012048

ENSMUSG00000017146

UniProt

P38398

P48754

RefSeq (mRNA)

NM_007294 NM_007295 NM_007296 NM_007297 NM_007298

NM_007299 NM_007300 NM_007301 NM_007302 NM_007303 NM_007305 NM_007306

NM_009764

RefSeq (protein)

NP_009225 NP_009228 NP_009229 NP_009230 NP_009231

NP_033894

Location (UCSC) Chr 17: 43.04 – 43.17 Mb Chr 11: 101.49 – 101.55 Mb

PubMed
PubMed
search [3] [4]

Wikidata

View/Edit Human View/Edit Mouse

BRCA1
BRCA1
and BRCA1
BRCA1
(/ˌbrækəˈwʌn/[5]) are a human gene and its protein product, respectively. The official symbol (BRCA1, italic for the gene, nonitalic for the protein) and the official name (breast cancer 1) are maintained by the HGNC. Orthologs, styled Brca1 and Brca1, are common in other mammal species.[6] BRCA1
BRCA1
is a human tumor suppressor gene[7][8] (to be specific, a caretaker gene), found in all humans; its protein, also called by the synonym breast cancer type 1 susceptibility protein, is responsible for repairing DNA.[9] BRCA1
BRCA1
and BRCA2
BRCA2
are unrelated proteins,[10] but both are normally expressed in the cells of breast and other tissue, where they help repair damaged DNA, or destroy cells if DNA
DNA
cannot be repaired. They are involved in the repair of chromosomal damage with an important role in the error-free repair of DNA
DNA
double-strand breaks.[11][12] If BRCA1
BRCA1
or BRCA2
BRCA2
itself is damaged by a BRCA mutation, damaged DNA
DNA
is not repaired properly, and this increases the risk for breast cancer.[13][14] BRCA1
BRCA1
and BRCA2
BRCA2
have been described as "breast cancer susceptibility genes" and "breast cancer susceptibility proteins". The predominant allele has a normal, tumor suppressive function whereas high penetrance mutations in these genes cause a loss of tumor suppressive function which correlates with an increased risk of breast cancer.[15] BRCA1
BRCA1
combines with other tumor suppressors, DNA
DNA
damage sensors and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC).[16] The BRCA1 protein
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
DNA
repair of double-strand breaks[14] ubiquitination, transcriptional regulation as well as other functions.[17] Methods to test for the likelihood of a patient with mutations in BRCA1
BRCA1
and BRCA2
BRCA2
developing cancer were covered by patents owned or controlled by Myriad Genetics.[18][19] Myriad's business model of offering the diagnostic test exclusively 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;[20] it also led to controversy over high prices and the inability to obtain second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology
Pathology
v. Myriad Genetics lawsuit.[21]

Contents

1 Discovery 2 Gene
Gene
location 3 Protein
Protein
structure

3.1 Zinc ring finger domain 3.2 Serine cluster domain 3.3 BRCT
BRCT
domains

4 Function and mechanism

4.1 Transcription

5 Mutations and cancer risk 6 Low expression of BRCA1
BRCA1
in breast and ovarian cancers

6.1 Mutation
Mutation
of BRCA1
BRCA1
in breast and ovarian cancer 6.2 BRCA1
BRCA1
promoter hypermethylation in breast and ovarian cancer 6.3 MicroRNA repression of BRCA1
BRCA1
in breast cancers 6.4 MicroRNA repression of BRCA1
BRCA1
in ovarian cancers 6.5 Deficiency of BRCA1
BRCA1
expression is likely tumorigenic

7 Germ line mutations and founder effect 8 Female fertility 9 Cancer
Cancer
chemotherapy 10 Patents, enforcement, litigation, and controversy 11 Interactions 12 References 13 External links

Discovery[edit] The first evidence for the existence of a gene encoding for a DNA repair enzyme involved in breast cancer susceptibility was provided by Mary-Claire King's laboratory at UC Berkeley in 1990.[22] Four years later, after an international race to find it,[23] the gene was cloned in 1994 by scientists at University of Utah, National Institute of Environmental Health Sciences (NIEHS) and Myriad Genetics.[18][24] Gene
Gene
location[edit] The human BRCA1
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).[25] BRCA1
BRCA1
orthologs[6] have been identified in most mammals for which complete genome data are available. Protein
Protein
structure[edit] The BRCA1 protein
BRCA1 protein
contains the following domains:[26]

Zinc finger, C3HC4 type ( RING
RING
finger) BRCA1
BRCA1
C Terminus (BRCT) domain

This protein also contains nuclear localization signals and nuclear export signal motifs.[27] The human BRCA1 protein
BRCA1 protein
consists of four major protein domains; the Znf C3HC4- RING
RING
domain, the BRCA1
BRCA1
serine domain and two BRCT
BRCT
domains. These domains encode approximately 27% of BRCA1
BRCA1
protein. There are six known isoforms of BRCA1,[28] with isoforms 1 and 2 comprising 1863 amino acids each.[citation needed] BRCA1
BRCA1
is unrelated to BRCA2, i.e. they are not homologs or paralogs.[10]

Domain map of BRCA1; RING, serine containing domain (SCD), and BRCT domains are indicated. Horizontal black lines indicate protein-binding domains for the listed partners. Red circles mark phosphorylation sites.[29]

Zinc ring finger domain[edit] The RING
RING
motif, a Zn finger
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.[30] This motif contains a short anti-parallel beta-sheet, two zinc-binding loops and a central alpha helix in a small domain. This RING
RING
domain interacts with associated proteins, including BARD1, which also contains a RING
RING
motif, to form a heterodimer. The BRCA1
BRCA1
RING
RING
motif is flanked by alpha helices formed by residues 8–22 and 81–96 of the BRCA1
BRCA1
protein. It interacts with a homologous region in BARD1
BARD1
also consisting of a RING
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 stabilize the BRCA1- BARD1
BARD1
heterodimer complex. Additional stabilization 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
BRCA1
tumor suppression.[30] The ring domain is an important element of ubiquitin E3 ligases, which catalyze protein ubiquitination. Ubiquitin
Ubiquitin
is a small regulatory protein found in all tissues that direct proteins to compartments within the cell. BRCA1
BRCA1
polypeptides, in particular, Lys-48-linked polyubiquitin chains are dispersed throughout the resting cell nucleus, but at the start of DNA
DNA
replication, they gather in restrained groups that also contain BRCA2
BRCA2
and BARD1. BARD1
BARD1
is thought to be involved in the recognition and binding of protein targets for ubiquitination.[31] It attaches to proteins and labels them for destruction. Ubiquitination occurs via the BRCA1
BRCA1
fusion protein and is abolished by zinc chelation.[30] The enzyme activity of the fusion protein is dependent on the proper folding of the ring domain.[citation needed] Serine cluster domain[edit] BRCA1
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
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
DNA
damage. Mutation
Mutation
of serine residues may affect localization of BRCA1
BRCA1
to sites of DNA
DNA
damage and DNA
DNA
damage response function.[29][32] BRCT
BRCT
domains[edit] The dual repeat BRCT domain
BRCT domain
of the BRCA1 protein
BRCA1 protein
is an elongated structure approximately 70 Å long and 30–35 Å wide.[33] The 85–95 amino acid domains in BRCT
BRCT
can be found as single modules or as multiple tandem repeats containing two domains.[34] Both of these possibilities can occur in a single protein in a variety of different conformations.[33] The C-terminal BRCT
BRCT
region of the BRCA1 protein
BRCA1 protein
is essential for repair of DNA, transcription regulation and tumor suppressor function.[35] In BRCA1
BRCA1
the dual tandem repeat BRCT
BRCT
domains are arranged in a head-to-tail-fashion in the three-dimensional structure, burying 1600 Å 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
DNA
damage. A missense mutation at the interface of these two proteins can perturb the cell cycle, resulting a greater risk of developing cancer. Function and mechanism[edit] BRCA1
BRCA1
is part of a complex that repairs double-strand breaks in DNA. The strands of the DNA
DNA
double helix are continuously breaking as they become damaged. Sometimes only one strand is broken, sometimes both strands are broken simultaneously. DNA
DNA
cross-linking agents are an important source of chromosome/ DNA
DNA
damage. Double-strand breaks
Double-strand breaks
occur as intermediates after the crosslinks are removed, and indeed, biallelic mutations in BRCA1
BRCA1
have been identified to be responsible for Fanconi Anemia, Complementation Group S,[36] a genetic disease associated with hypersensitivity to DNA
DNA
crosslinking agents. BRCA1
BRCA1
is part of a protein complex that repairs DNA
DNA
when both strands are broken. When this happens, it is difficult for the repair mechanism to "know" how to replace the correct DNA
DNA
sequence, and there are multiple ways to attempt the repair. The double-strand repair mechanism in which BRCA1
BRCA1
participates is homology-directed repair, where the repair proteins copy the identical sequence from the intact sister chromatid.[37] In the nucleus of many types of normal cells, the BRCA1
BRCA1
protein interacts with RAD51
RAD51
during repair of DNA
DNA
double-strand breaks.[38] 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
RAD51
protein. By influencing DNA
DNA
damage repair, these three proteins play a role in maintaining the stability of the human genome.[citation needed] BRCA1
BRCA1
is also involved in another type of DNA
DNA
repair, termed mismatch repair. BRCA1
BRCA1
interacts with the DNA
DNA
mismatch repair protein MSH2.[39] MSH2, MSH6, PARP and some other proteins involved in single-strand repair are reported to be elevated in BRCA1-deficient mammary tumors.[40] A protein called valosin-containing protein (VCP, also known as p97) plays a role to recruit BRCA1
BRCA1
to the damaged DNA
DNA
sites. After ionizing radiation, VCP is recruited to DNA
DNA
lesions and cooperates with the ubiquitin ligase RNF8 to orchestrate assembly of signaling complexes for efficient DSB repair.[41] BRCA1
BRCA1
interacts with VCP.[42] BRCA1
BRCA1
also interacts with c-Myc, and other proteins that are critical to maintain genome stability.[43] BRCA1
BRCA1
directly binds to DNA, with higher affinity for branched DNA structures. This ability to bind to DNA
DNA
contributes to its ability to inhibit the nuclease activity of the MRN complex as well as the nuclease activity of Mre11 alone.[44] This may explain a role for BRCA1
BRCA1
to promote lower fidelity DNA
DNA
repair by non-homologous end joining (NHEJ).[45] BRCA1
BRCA1
also colocalizes with γ-H2AX (histone H2AX phosphorylated on serine-139) in DNA
DNA
double-strand break repair foci, indicating it may play a role in recruiting repair factors.[17][46] Formaldehyde
Formaldehyde
and acetaldehyde are common environmental sources of DNA cross links that often require repairs mediated by BRCA1
BRCA1
containing pathways.[47][48] This DNA
DNA
repair function is essential; mice with loss-of-function mutations in both BRCA1
BRCA1
alleles are not viable, and as of 2015 only two adults were known to have loss-of-function mutations in both alleles; both had congenital or developmental issues, and both had cancer. One was presumed to have survived to adulthood because one of the BRCA1
BRCA1
mutations was hypomorphic.[49] Transcription[edit] BRCA1
BRCA1
was shown to co-purify with the human RNA Polymerase II holoenzyme in HeLa extracts, implying it is a component of the holoenzyme.[50] Later research, however, contradicted this assumption, instead showing that the predominant complex including BRCA1
BRCA1
in HeLa cells is a 2 megadalton complex containing SWI/SNF.[51] SWI/SNF is a chromatin remodeling complex. Artificial tethering of BRCA1
BRCA1
to chromatin was shown to decondense heterochromatin, though the SWI/SNF interacting domain was not necessary for this role.[46] BRCA1 interacts with the NELF-B (COBRA1) subunit of the NELF complex.[46] Mutations and cancer risk[edit] Further information: BRCA mutation Certain variations of the BRCA1
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
BRCA1
gene, many of which are associated with an increased risk of cancer. Females with an abnormal BRCA1
BRCA1
or BRCA2
BRCA2
gene have up to an 80% risk of developing breast cancer by age 90; increased risk of developing ovarian cancer is about 55% for females with BRCA1
BRCA1
mutations and about 25% for females with BRCA2
BRCA2
mutations.[52] These mutations can be changes in one or a small number of DNA
DNA
base pairs (the building-blocks of DNA), and can be identified with PCR and DNA
DNA
sequencing.[citation needed] In some cases, large segments of DNA
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 mutation detection (sequencing) are unable to reveal these types of mutation.[53] Other methods have been proposed: traditional quantitative PCR,[54] Multiplex Ligation-dependent Probe Amplification (MLPA),[55] and Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF).[56] Newer methods have also been recently proposed: heteroduplex analysis (HDA) by multi-capillary electrophoresis or also dedicated oligonucleotides array based on comparative genomic hybridization (array-CGH).[57] Some results suggest that hypermethylation of the BRCA1
BRCA1
promoter, which has been reported in some cancers, could be considered as an inactivating mechanism for BRCA1
BRCA1
expression.[58] A mutated BRCA1
BRCA1
gene usually makes a protein that does not function properly. Researchers believe that the defective BRCA1 protein
BRCA1 protein
is unable to help fix DNA
DNA
damage leading to mutations in other genes. These mutations can accumulate and may allow cells to grow and divide uncontrollably to form a tumor. Thus, BRCA1
BRCA1
inactivating mutations lead to a predisposition for cancer.[citation needed] Template:Http://exogenbio.com/dna-damage-and-cancer/ citation added BRCA1
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.[59] In addition to breast cancer, mutations in the BRCA1
BRCA1
gene also increase the risk of ovarian and prostate cancers. Moreover, precancerous lesions (dysplasia) within the Fallopian tube
Fallopian tube
have been linked to BRCA1
BRCA1
gene mutations. Pathogenic mutations anywhere in a model pathway containing BRCA1
BRCA1
and BRCA2
BRCA2
greatly increase risks for a subset of leukemias and lymphomas.[14] Females having inherited a defective BRCA1
BRCA1
or BRCA2
BRCA2
gene has 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, may 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
BRCA1
or BRCA2. A major advantage of this model is that it suggests there may be some options in addition to prophylactic surgery.[60] Low expression of BRCA1
BRCA1
in breast and ovarian cancers[edit] BRCA1
BRCA1
expression is reduced or undetectable in the majority of high grade, ductal breast cancers.[61] It has long been noted that loss of BRCA1
BRCA1
activity, either by germ-line mutations or by down-regulation of gene expression, leads to tumor formation in specific target tissues. In particular, decreased BRCA1
BRCA1
expression contributes to both sporadic and inherited breast tumor progression.[62] Reduced expression of BRCA1
BRCA1
is tumorigenic because it plays an important role in the repair of DNA
DNA
damages, especially double-strand breaks, by the potentially error-free pathway of homologous recombination.[63] Since cells that lack the BRCA1 protein
BRCA1 protein
tend to repair DNA
DNA
damages by alternative more error-prone mechanisms, the reduction or silencing of this protein generates mutations and gross chromosomal rearrangements that can lead to progression to breast cancer.[63] Similarly, BRCA1
BRCA1
expression is low in the majority (55%) of sporadic epithelial ovarian cancers (EOCs) where EOCs are the most common type of ovarian cancer, representing approximately 90% of ovarian cancers.[64] In serous ovarian carcinomas, a sub-category constituting about 2/3 of EOCs, low BRCA1
BRCA1
expression occurs in more than 50% of cases.[65] Bowtell[66] reviewed the literature indicating that deficient homologous recombination repair caused by BRCA1
BRCA1
deficiency is tumorigenic. In particular this deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy. Especially noted was that BRCA1
BRCA1
deficiency could be the cause of tumorigenesis whether due to BRCA1
BRCA1
mutation or any other event that causes a deficiency of BRCA1
BRCA1
expression. Mutation
Mutation
of BRCA1
BRCA1
in breast and ovarian cancer[edit] Only about 3%–8% of all women with breast cancer carry a mutation in BRCA1
BRCA1
or BRCA2.[67] Similarly, BRCA1
BRCA1
mutations are only seen in about 18% of ovarian cancers (13% germline mutations and 5% somatic mutations).[68] Thus, while BRCA1
BRCA1
expression is low in the majority of these cancers, BRCA1
BRCA1
mutation is not a major cause of reduced expression. BRCA1
BRCA1
promoter hypermethylation in breast and ovarian cancer[edit] BRCA1
BRCA1
promoter hypermethylation was present in only 13% of unselected primary breast carcinomas.[69] Similarly, BRCA1
BRCA1
promoter hypermethylation was present in only 5% to 15% of EOC cases.[64] Thus, while BRCA1
BRCA1
expression is low in these cancers, BRCA1
BRCA1
promoter methylation is only a minor cause of reduced expression. MicroRNA repression of BRCA1
BRCA1
in breast cancers[edit] There are a number of specific microRNAs, when overexpressed, that directly reduce expression of specific DNA
DNA
repair proteins (see MicroRNA section DNA
DNA
repair and cancer) In the case of breast cancer, microRNA-182 (miR-182) specifically targets BRCA1.[70] Breast
Breast
cancers can be classified based on receptor status or histology, with triple-negative breast cancer (15%–25% of breast cancers), HER2+ (15%–30% of breast cancers), ER+/PR+ (about 70% of breast cancers), and Invasive lobular carcinoma
Invasive lobular carcinoma
(about 5%–10% of invasive breast cancer). All four types of breast cancer were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue.[71] In breast cancer cell lines, there is an inverse correlation of BRCA1 protein
BRCA1 protein
levels with miR-182 expression.[70] Thus it appears that much of the reduction or absence of BRCA1
BRCA1
in high grade ductal breast cancers may be due to over-expressed miR-182. In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1
BRCA1
expression. These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1
BRCA1
inactivation.[72] Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1
BRCA1
in these triple-negative breast cancers. MicroRNA repression of BRCA1
BRCA1
in ovarian cancers[edit] In both serous tubal intraepithelial carcinoma (the precursor lesion to high grade serous ovarian carcinoma (HG-SOC)), and in HG-SOC itself, miR-182 is overexpressed in about 70% of cases.[73] In cells with over-expressed miR-182, BRCA1
BRCA1
remained low, even after exposure to ionizing radiation (which normally raises BRCA1
BRCA1
expression).[73] Thus much of the reduced or absent BRCA1
BRCA1
in HG-SOC may be due to over-expressed miR-182. Another microRNA known to reduce expression of BRCA1
BRCA1
in ovarian cancer cells is miR-9.[64] Among 58 tumors from patients with stage IIIC or stage IV serous ovarian cancers (HG-SOG), an inverse correlation was found between expressions of miR-9 and BRCA1,[64] so that increased miR-9 may also contribute to reduced expression of BRCA1
BRCA1
in these ovarian cancers. Deficiency of BRCA1
BRCA1
expression is likely tumorigenic[edit] DNA
DNA
damage appears to be the primary underlying cause of cancer,[74][75] and deficiencies in DNA
DNA
repair appears to underlie many forms of cancer.[76] If DNA
DNA
repair is deficient, DNA
DNA
damage tends to accumulate. Such excess DNA
DNA
damage may increase mutational errors during DNA
DNA
replication due to error-prone translesion synthesis. Excess DNA
DNA
damage may also increase epigenetic alterations due to errors during DNA
DNA
repair.[77][78] Such mutations and epigenetic alterations may give rise to cancer. The frequent microRNA-induced deficiency of BRCA1
BRCA1
in breast and ovarian cancers likely contribute to the progression of those cancers. Germ line mutations and founder effect[edit] All germ-line BRCA1
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.[79] Examples of manifestations of a founder effect are seen among Ashkenazi Jews. Three mutations in BRCA1
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
BRCA1
gene.[80][81] In fact, it has been shown that if a Jewish woman does not carry a BRCA1 185delAG, BRCA1
BRCA1
5382insC founder mutation, it is highly unlikely that a different BRCA1
BRCA1
mutation will be found.[82] Additional examples of founder mutations in BRCA1
BRCA1
are given in Table 1 (mainly derived from [79]). This is a dynamic list and may never be able to satisfy particular standards for completeness. You can help by expanding it with reliably sourced entries.

Population or subgroup BRCA1
BRCA1
mutation(s)[83] Reference(s)

African-Americans 943ins10, M1775R [84]

Afrikaners E881X [85]

Ashkenazi Jewish 185delAG, 188del11, 5382insC [80][81]

Austrians 2795delA, C61G, 5382insC, Q1806stop [86]

Belgians 2804delAA, IVS5+3A>G [87][88]

Dutch Exon 2 deletion, exon 13 deletion, 2804delAA [87][89][90]

Finns 3745delT, IVS11-2A>G [91][92]

French 3600del11, G1710X [93]

French Canadians C4446T [94]

Germans 5382insC, 4184del4 [95][96]

Greeks 5382insC [97]

Hungarians 300T>G, 5382insC, 185delAG [98]

Italians 5083del19 [99]

Japanese L63X, Q934X [100]

Native North Americans 1510insG, 1506A>G [101]

Northern Irish 2800delAA [102]

Norwegians 816delGT, 1135insA, 1675delA, 3347delAG [103][104]

Pakistanis 2080insA, 3889delAG, 4184del4, 4284delAG, IVS14-1A>G [105]

Polish 300T>G, 5382insC, C61G, 4153delA [106][107]

Russians 5382insC, 4153delA [108]

Scottish 2800delAA [102][109]

Spanish R71G [110][111]

Swedish Q563X, 3171ins5, 1201del11, 2594delC [84][112]

Female fertility[edit] As women age, reproductive performance declines, leading to menopause. This decline is tied to a reduction in the number of ovarian follicles. Although about 1 million oocytes are present at birth in the human ovary, only about 500 (about 0.05%) of these ovulate. The decline in ovarian reserve appears to occur at a constantly increasing rate with age,[113] and leads to nearly complete exhaustion of the reserve by about age 52. As ovarian reserve and fertility decline with age, there is also a parallel increase in pregnancy failure and meiotic errors, resulting in chromosomally abnormal conceptions.[114] Women with a germ-line BRCA1
BRCA1
mutation appear to have a diminished oocyte reserve and decreased fertility compared to normally aging women.[115] Furthermore, women with an inherited BRCA1
BRCA1
mutation undergo menopause prematurely.[116] Since BRCA1
BRCA1
is a key DNA
DNA
repair protein, these findings suggest that naturally occurring DNA
DNA
damages in oocytes are repaired less efficiently in women with a BRCA1
BRCA1
defect, and that this repair inefficiency leads to early reproductive failure.[115] As noted above, the BRCA1 protein
BRCA1 protein
plays a key role in homologous recombinational repair. This is the only known cellular process that can accurately repair DNA
DNA
double-strand breaks. DNA
DNA
double-strand breaks accumulate with age in humans and mice in primordial follicles.[117] Primordial follicles contain oocytes that are at an intermediate (prophase I) stage of meiosis. Meiosis
Meiosis
is the general process in eukaryotic organisms by which germ cells are formed, and it is likely an adaptation for removing DNA
DNA
damages, especially double-strand breaks, from germ line DNA.[118] (Also see article Meiosis). Homologous recombinational repair employing BRCA1
BRCA1
is especially promoted during meiosis. It was found that expression of 4 key genes necessary for homologous recombinational repair of DNA double-strand breaks (BRCA1, MRE11, RAD51
RAD51
and ATM) decline with age in the oocytes of humans and mice,[117] leading to the hypothesis that DNA
DNA
double-strand break repair is necessary for the maintenance of oocyte reserve and that a decline in efficiency of repair with age plays a role in ovarian aging. Cancer
Cancer
chemotherapy[edit] Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. At diagnosis, almost 70% of persons with NSCLC have locally advanced or metastatic disease. Persons with NSCLC are often treated with therapeutic platinum compounds (e.g. cisplatin, carboplatin or oxaliplatin) that cause inter-strand cross-links in DNA. Among individuals with NSCLC, low expression of BRCA1
BRCA1
in the primary tumor correlated with improved survival after platinum-containing chemotherapy.[119][120] This correlation implies that low BRCA1
BRCA1
in cancer, and the consequent low level of DNA
DNA
repair, causes vulnerability of cancer to treatment by the DNA
DNA
cross-linking agents. High BRCA1
BRCA1
may protect cancer cells by acting in a pathway that removes the damages in DNA
DNA
introduced by the platinum drugs. Thus the level of BRCA1
BRCA1
expression is a potentially important tool for tailoring chemotherapy in lung cancer management.[119][120] Level of BRCA1
BRCA1
expression is also relevant to ovarian cancer treatment. Patients having sporadic ovarian cancer who were treated with platinum drugs had longer median survival times if their BRCA1 expression was low compared to patients with higher BRCA1
BRCA1
expression (46 compared to 33 months).[121] Patents, enforcement, litigation, and controversy[edit] Main article: Association for Molecular Pathology
Pathology
v. Myriad Genetics A patent application for the isolated BRCA1
BRCA1
gene and 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;[18] 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
BRCA2
gene and identified key mutations, and the first BRCA2
BRCA2
patent was filed in the U.S. by Myriad and other institutions in 1995.[19] Myriad is the exclusive licensee of these patents and has enforced them in the US against clinical diagnostic labs.[21] 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;[20] 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
Pathology
v. Myriad Genetics lawsuit.[21][122] The patents began 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-provider status."[123][124] Peter Meldrum, CEO of Myriad Genetics, has acknowledged that Myriad has "other competitive advantages that may make such [patent] enforcement unnecessary" in Europe.[125] As with any gene, finding variation in BRCA1
BRCA1
is not hard. The real value comes from understanding what the clinical consequences of any particular variant are. Myriad has a large, proprietary database of such genotype-phenotype correlations. In response, parallel open-source databases are being developed. Legal decisions surrounding the BRCA1
BRCA1
and BRCA2
BRCA2
patents will affect the field of genetic testing in general.[126] A June 2013 article, in Association for Molecular Pathology
Pathology
v. Myriad Genetics (No. 12-398), quoted the US Supreme Court's unanimous ruling that, "A naturally occurring DNA
DNA
segment is a product of nature and not patent eligible merely because it has been isolated," invalidating Myriad's patents on the BRCA1
BRCA1
and BRCA2
BRCA2
genes. However, the Court also held that manipulation of a gene to create something not found in nature could still be eligible for patent protection.[127] The Federal Court of Australia came to the opposite conclusion, upholding the validity of an Australian Myriad Genetics patent over the BRCA1
BRCA1
gene in February 2013.[128] The Federal Court also rejected an appeal in September 2014.[129] Yvonne D’Arcy won her case against US-based biotech company Myriad Genetics in the High Court of Australia. In their unanimous decision on October 7, 2015 the "high court found that an isolated nucleic acid, coding for a BRCA1
BRCA1
protein, with specific variations from the norm that are indicative of susceptibility to breast cancer and ovarian cancer was not a 'patentable invention.'"[130] Interactions[edit] BRCA1
BRCA1
has been shown to interact with the following proteins:

ABL1,[131] AKT1,[132][133] AR,[134] ATR,[135][136][137][138] ATM,[16][135][136][137][138][139][140] ATF1,[141] AURKA,[142] BACH1,[143] BARD1,[30][39][43][143][144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159][160][161][162][163][164][165][166][167][168][169][170][171] BRCA2,[149][172][173][174] BRCC3,[149] BRE,[149] BRIP1,[35][175][176][177][178][179] C-jun,[180] CHEK2,[181][182] CLSPN,[183] COBRA1,[184] CREBBP,[169][185][186][187][188] CSNK2B,[189] CSTF2,[154][155] CDK2,[190][191][192] DHX9,[193][194] ELK4,[195] EP300,[185][187] ESR1,[187][196][197][198] FANCA,[199] FANCD2,[151][173] FHL2,[200][201] H2AFX,[144][148][202] JUNB,[180] JunD,[180] LMO4,[203][204] MAP3K3,[205] MED1,[176] MED17,[159][176][206] MED21,[207] MED24,[176] MRE11A,[16][159][208][209] MSH2,[16][39] MSH3,[39][175] MSH6,[16][39] Myc,[43][210][211][212] NBN,[16][159][208] NMI,[210] NPM1,[150] NCOA2,[175][213] NUFIP1,[214] P53,[149][186][215][216][217] PALB2,[218] POLR2A,[159][207][219][220] PPP1CA,[221] Rad50,[16][159][208] RAD51,[39][149][172][222] RBBP4,[223] RBBP7,[223][224][225] RBBP8,[165][175][226][227][228][229][230] RELA,[169] RB1,[223][231][232] RBL1,[231] RBL2,[231] RPL31,[225] SMARCA4,[233][234] SMARCB1,[233] STAT1,[235] UBE2D1,[144][145][146][147][148][149][150][151][152][153] USF2,[236] VCP,[237] XIST,[238][239] and ZNF350.[240]

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functional activity and regulation of RB family but not RB protein binding". Oncogene. 20 (35): 4827–41. doi:10.1038/sj.onc.1204666. PMID 11521194.  ^ Aprelikova ON, Fang BS, Meissner EG, Cotter S, Campbell M, Kuthiala A, Bessho M, Jensen RA, Liu ET (October 1999). "BRCA1-associated growth arrest is RB-dependent". Proc. Natl. Acad. Sci. U.S.A. 96 (21): 11866–71. doi:10.1073/pnas.96.21.11866. PMC 18378 . PMID 10518542.  ^ a b Bochar DA, Wang L, Beniya H, Kinev A, Xue Y, Lane WS, Wang W, Kashanchi F, Shiekhattar R (July 2000). " BRCA1
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External links[edit]

Wikimedia Commons has media related to BRCA1.

BRCA1
BRCA1
Protein
Protein
at the US National Library of Medicine
Medicine
Medical Subject Headings (MeSH) Genes, BRCA1
BRCA1
at the US National Library of Medicine
Medicine
Medical Subject Headings (MeSH)

v t e

PDB gallery

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

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

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

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

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

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

1t2u: Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1: structure of BRCA1
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
BRCT
repeats of BRCA1
BRCA1
bound to a CtIP phosphopeptide. 

v t e

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