Biology:BRCA2

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Short description: Gene known for its role in breast cancer


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

BRCA2 and BRCA2 (/ˌbrækəˈtuː/[1]) are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) are maintained by the HUGO Gene Nomenclature Committee. One alternative symbol, FANCD1, recognizes its association with the FANC protein complex. Orthologs, styled Brca2 and Brca2, are common in other vertebrate species.[2][3] BRCA2 is a human tumor suppressor gene[4][5] (specifically, a caretaker gene), found in all humans; its protein, also called by the synonym breast cancer type 2 susceptibility protein, is responsible for repairing DNA.[6]

BRCA2 and BRCA1 are normally expressed in the cells of breast and other tissue, where they help repair damaged DNA or destroy cells if DNA cannot be repaired. They are involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double strand breaks.[7][8] If BRCA1 or BRCA2 itself is damaged by a BRCA mutation, damaged DNA is not repaired properly, and this increases the risk for breast cancer.[9][10] BRCA1 and 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.[11]

The BRCA2 gene is located on the long (q) arm of chromosome 13 at position 12.3 (13q12.3).[12] The human reference BRCA2 gene contains 27 exons, and the cDNA has 10,254 base pairs[13] coding for a protein of 3418 amino acids.[14][15]

Function

Recombinational repair of DNA double-strand damage - some key steps. ATM (ATM) is a protein kinase that is recruited and activated by DNA double-strand breaks. DNA double-strand damages also activate the Fanconi anemia core complex (FANCA/B/C/E/F/G/L/M).[16] The FA core complex monoubiquitinates the downstream targets FANCD2 and FANCI.[17] ATM activates (phosphorylates) CHEK2 and FANCD2[18] CHEK2 phosphorylates BRCA1.[19] Ubiquinated FANCD2 complexes with BRCA1 and RAD51.[20] The PALB2 protein acts as a hub,[21] bringing together BRCA1, BRCA2 and RAD51 at the site of a DNA double-strand break, and also binds to RAD51C, a member of the RAD51 paralog complex RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2). The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.[22] RAD51 plays a major role in homologous recombinational repair of DNA during double strand break repair. In this process, an ATP dependent DNA strand exchange takes place in which a single strand invades base-paired strands of homologous DNA molecules. RAD51 is involved in the search for homology and strand pairing stages of the process.

Although the structures of the BRCA1 and BRCA2 genes are very different, at least some functions are interrelated. The proteins made by both genes are essential for repairing damaged DNA (see Figure of recombinational repair steps). BRCA2 binds the single strand DNA and directly interacts with the recombinase RAD51 to stimulate[23] and maintain [24] strand invasion, a vital step of homologous recombination. The localization of RAD51 to the DNA double-strand break requires the formation of the BRCA1-PALB2-BRCA2 complex. PALB2 (Partner and localizer of BRCA2)[25] can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion.[26] These breaks can be caused by natural and medical radiation or other environmental exposures, but also occur when chromosomes exchange genetic material during a special type of cell division that creates sperm and eggs (meiosis). Double strand breaks are also generated during repair of DNA cross links. By repairing DNA, these proteins play a role in maintaining the stability of the human genome and prevent dangerous gene rearrangements that can lead to hematologic and other cancers.

BRCA2 has been shown to possess a crucial role in protection from the MRE11-dependent nucleolytic degradation of the reversed forks that are forming during DNA replication fork stalling (caused by obstacles such as mutations, intercalating agents etc.).[27]

Like BRCA1, BRCA2 probably regulates the activity of other genes and plays a critical role in embryo development.

Clinical significance

Absolute risk of cancers in BRCA1 or BRCA2 mutation.[28]
Further information: Medicine:BRCA mutation

Certain variations of the BRCA2 gene increase risks for breast cancer as part of a hereditary breast–ovarian cancer syndrome. Researchers have identified hundreds of mutations in the BRCA2 gene, many of which cause an increased risk of cancer. BRCA2 mutations are usually insertions or deletions of a small number of DNA base pairs in the gene. As a result of these mutations, the protein product of the BRCA2 gene is abnormal, and does not function properly. Researchers believe that the defective BRCA2 protein is unable to fix DNA damage that occurs throughout the genome. As a result, there is an increase in mutations due to error-prone translesion synthesis past un-repaired DNA damage, and some of these mutations can cause cells to divide in an uncontrolled way and form a tumor.

People who have two mutated copies of the BRCA2 gene have one type of Fanconi anemia. This condition is caused by extremely reduced levels of the BRCA2 protein in cells, which allows the accumulation of damaged DNA. Patients with Fanconi anemia are prone to several types of leukemia (a type of blood cell cancer); solid tumors, particularly of the head, neck, skin, and reproductive organs; and bone marrow suppression (reduced blood cell production that leads to anemia). 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- and BRCA2-associated 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 carcinogens and an infectious process. An innate genomic deficit 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 are some options in addition to prophylactic surgery.[29]

In addition to breast cancer in men and women, mutations in BRCA2 also lead to an increased risk of ovarian, uterine tube, prostate and pancreatic cancer. In some studies, mutations in the central part of the gene have been associated with a higher risk of ovarian cancer and a lower risk of prostate cancer than mutations in other parts of the gene. Several other types of cancer have also been seen in certain families with BRCA2 mutations.

In general, strongly inherited gene mutations (including mutations in BRCA2) account for only 5-10% of breast cancer cases; the specific risk of getting breast or other cancer for anyone carrying a BRCA2 mutation depends on many factors.[30]

History

The BRCA2 gene was discovered in 1994.[31][12][32] In 1996, Kenneth Offit and his research group at Memorial Sloan Kettering Cancer Center successfully identified the most common mutation on the gene associated with breast and ovarian cancer among individuals of Ashkenazi Jewish ancestry.[33][34][35][36]

The gene was first cloned by scientists at Myriad Genetics, Endo Recherche, Inc., HSC Research & Development Limited Partnership, and the University of Pennsylvania.[37]

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.[38][39] Myriad's business model of exclusively offering the diagnostic test led from Myriad's beginnings as a startup in 1994 to its being a publicly traded company with 1200 employees and about $500M in annual revenue in 2012;[40] it also led to controversy over high test prices and the unavailability of second opinions from other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v. Myriad Genetics lawsuit.[41]

Germline mutations and founder effect

All germline BRCA2 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 theoretically be traced back to a common ancestor. Given the complexity of mutation screening for BRCA2, 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] A striking example of a founder mutation is found in Iceland, where a single BRCA2 (999del5) mutation accounts for virtually all breast/ovarian cancer families.[43][44] This frame-shift mutation leads to a highly truncated protein product. In a large study examining hundreds of cancer and control individuals, this 999del5 mutation was found in 0.6% of the general population. Of note, while 72% of patients who were found to be carriers had a moderate or strong family history of breast cancer, 28% had little or no family history of the disease. This strongly suggests the presence of modifying genes that affect the phenotypic expression of this mutation, or possibly the interaction of the BRCA2 mutation with environmental factors. Additional examples of founder mutations in BRCA2 are given in the table below.

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 BRCA2 mutation(s)[42][45] Reference(s)
Ashkenazi Jewish 6174delT [46]
Dutch 5579insA [47]
Finns 8555T>G, 999del5, IVS23-2A>G [48][49]
French Canadians 8765delAG, 3398delAAAAG [50][51][52]
Hungarians 9326insA [53]
Icelanders 999del5 [43][44]
Italians 8765delAG [54]
Northern Irish 6503delTT [55]
Pakistanis 3337C>T [56]
Scottish 6503delTT [55]
Slovenians IVS16-2A>G [57]
Spanish 3034delAAAC(codon936), 9254del5 [58]
Swedish 4486delG [59]

Meiosis

In the plant Arabidopsis thaliana, loss of the BRCA2 homolog AtBRCA2 causes severe defects in both male meiosis and in the development of the female gametocyte.[60] AtBRCA2 protein is required for proper localization of the synaptonemal complex protein AtZYP1 and the recombinases AtRAD51 and AtDMC1. Furthermore, AtBRCA2 is required for proper meiotic synapsis. Thus AtBRCA2 is likely important for meiotic recombination. It appears that AtBRCA2 acts during meiosis to control the single-strand invasion steps mediated by AtRAD51 and AtDMC1 occurring during meiotic homologous recombinational repair of DNA damages.[60]

Homologs of BRCA2 are also essential for meiosis in the fungus Ustilago maydis,[61] the worm Caenorhabditis elegans,[62][63] and the fruitfly Drosophila melanogaster.[64]

Mice that produce truncated versions of BRCA2 are viable but sterile.[65] BRCA2 mutant rats have a phenotype of growth inhibition and sterility in both sexes.[66] Aspermatogenesis in these mutant rats is due to a failure of homologous chromosome synapsis during meiosis.

BRC repeat sequences

DMC1 (DNA meiotic recombinase 1) is a meiosis specific homolog of RAD51 that mediates strand exchange during homologous recombinational repair. DMC1 promotes the formation of DNA strand invasion products (joint molecules) between homologous DNA molecules. Human DMC1 interacts directly with each of a series of repeat sequences in the BRCA2 protein (called BRC repeats) that stimulate joint molecule formation by DMC1.[67] BRC repeats conform to a motif consisting of a sequence of about 35 highly conserved amino acids that are present at least once in all BRCA2-like proteins. The BRCA2 BRC repeats stimulate joint molecule formation by promoting the interaction of single-stranded DNA (ssDNA) with DMC1.[67] The ssDNA complexed with DMC1 can pair with homologous ssDNA from another chromosome during the synopsis stage of meiosis to form a joint molecule, a central step in homologous recombination. Thus the BRC repeat sequences of BRCA2 appear to play a key role in recombinational repair of DNA damages during meiotic recombination.

Overall, it appears that homologous recombination during meiosis functions to repair DNA damages,[citation needed] and that BRCA2 plays a key role in performing this function.

Neurogenesis

BRCA2 is required in the mouse for neurogenesis and suppression of medulloblastoma.[68] ‘’BRCA2’’ loss profoundly affects neurogenesis, particularly during embryonic and postnatal neural development. These neurological defects arise from DNA damage.[68]

Epigenetic control

Epigenetic alterations in expression of BRCA2 (causing over-expression or under-expression) are very frequent in sporadic cancers (see Table below) while mutations in BRCA2 are rarely found.[69][70][71]

In non-small cell lung cancer, BRCA2 is epigenetically repressed by hypermethylation of the promoter.[72] In this case, promoter hypermethylation is significantly associated with low mRNA expression and low protein expression but not with loss of heterozygosity of the gene.

In sporadic ovarian cancer, an opposite effect is found. BRCA2 promoter and 5'-UTR regions have relatively few or no methylated CpG dinucleotides in the tumor DNA compared with that of non-tumor DNA, and a significant correlation is found between hypomethylation and a >3-fold over-expression of BRCA2.[73] This indicates that hypomethylation of the BRCA2 promoter and 5'-UTR regions leads to over-expression of BRCA2 mRNA.

One report indicated some epigenetic control of BRCA2 expression by the microRNAs miR-146a and miR-148a.[74]

BRCA2 expression in cancer

In eukaryotes, BRCA2 protein has an important role in homologous recombinational repair. In mice and humans, BRCA2 primarily mediates orderly assembly of RAD51 on single-stranded (ss) DNA, the form that is active for homologous pairing and strand invasion.[75] BRCA2 also redirects RAD51 from double-stranded DNA and prevents dissociation from ssDNA.[75] In addition, the four paralogs of RAD51, consisting of RAD51B (RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3), XRCC2 form a complex called the BCDX2 complex (see Figure: Recombinational repair of DNA). This complex participates in RAD51 recruitment or stabilization at damage sites.[22] The BCDX2 complex appears to act by facilitating the assembly or stability of the RAD51 nucleoprotein filament. RAD51 catalyses strand transfer between a broken sequence and its undamaged homologue to allow re-synthesis of the damaged region (see homologous recombination models).

Some studies of cancers report over-expressed BRCA2 whereas other studies report under-expression of BRCA2. At least two reports found over-expression in some sporadic breast tumors and under-expression in other sporadic breast tumors.[76][77] (see Table).

Many cancers have epigenetic deficiencies in various DNA repair genes (see Frequencies of epimutations in DNA repair genes in cancers). These repair deficiencies likely cause increased unrepaired DNA damages. The over-expression of BRCA2 seen in many cancers may reflect compensatory BRCA2 over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages. Egawa et al.[78] suggest that increased expression of BRCA2 can be explained by the genomic instability frequently seen in cancers, which induces BRCA2 mRNA expression due to an increased need for BRCA2 for DNA repair.

Under-expression of BRCA2 would itself lead to increased unrepaired DNA damages. Replication errors past these damages (see translesion synthesis) would lead to increased mutations and cancer.

BRCA2 expression in sporadic cancers
Cancer Over or Under expression Frequency of altered expression Evaluation method Ref.
Sporadic ovarian cancer Over-expression 80% messenger RNA [73]
Sporadic ovarian cancer Under-expression 42% immunohistochemistry [79]
(recurrent cancer in study above) Increased-expression 71% immunohistochemistry [79]
Non-small cell lung cancer Under-expression 34% immunohistochemistry [72]
Breast cancer Over-expression 66% messenger RNA [78]
Breast cancer Over-expression 20% messenger RNA [76]
(same study as above) Under-expression 11% messenger RNA [76]
Breast cancer Over-expression 30% immunohistochemistry [77]
(same study as above) Under-expression 30% immunohistochemistry [77]
Triple negative breast cancer Under-expression 90% immunohistochemistry [80]

Interactions

BRCA2 has been shown to interact with


Domain architecture

BRCA2 repeat
PDB 1n0w EBI.jpg
crystal structure of a rad51-brca2 brc repeat complex
Identifiers
SymbolBRCA2
PfamPF00634
InterProIPR002093
SCOP21n0w / SCOPe / SUPFAM

BRCA2 contains a number of 39 amino acid repeats that are critical for binding to RAD51 (a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment.[97][104][105][113]

The BRCA2 helical domain adopts a helical structure, consisting of a four-helix cluster core (alpha 1, alpha 8, alpha 9, alpha 10) and two successive beta-hairpins (beta 1 to beta 4). An approximately 50-amino acid segment that contains four short helices (alpha 2 to alpha 4), meanders around the surface of the core structure. In BRCA2, the alpha 9 and alpha 10 helices pack with the BRCA2 OB1 domain through van der Waals contacts involving hydrophobic and aromatic residues, and also through side-chain and backbone hydrogen bonds. This domain binds the 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein, which was originally identified as one of three genes that map to a 1.5-Mb locus deleted in an inherited developmental malformation syndrome.[111]

The BRCA OB1 domain assumes an OB fold, which consists of a highly curved five-stranded beta-sheet that closes on itself to form a beta-barrel. OB1 has a shallow groove formed by one face of the curved sheet and is demarcated by two loops, one between beta 1 and beta 2 and another between beta 4 and beta 5, which allows for weak single strand DNA binding. The domain also binds the 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein.[111]

The BRCA OB3 domain assumes an OB fold, which consists of a highly curved five-stranded beta-sheet that closes on itself to form a beta-barrel. OB3 has a pronounced groove formed by one face of the curved sheet and is demarcated by two loops, one between beta 1 and beta 2 and another between beta 4 and beta 5, which allows for strong ssDNA binding.[111]

The Tower domain adopts a secondary structure consisting of a pair of long, antiparallel alpha-helices (the stem) that support a three-helix bundle (3HB) at their end. The 3HB contains a helix-turn-helix motif and is similar to the DNA binding domains of the bacterial site-specific recombinases, and of eukaryotic Myb and homeodomain transcription factors. The Tower domain has an important role in the tumour suppressor function of BRCA2, and is essential for appropriate binding of BRCA2 to DNA.[111] Studies shown that conformation of this tower domain is allosterically controlled by a small protein "DSS1", which interacts with helical, OB1 and OB2 domains of BRCA2.[114]

Patents, enforcement, litigation, and controversy

A patent application for the isolated BRCA1 gene and cancer-cancer promoting mutations, 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;[38] over the next year, Myriad, in collaboration with other investigators, isolated and sequenced the BRCA2 gene and identified relevant mutations, and the first BRCA2 patent was filed in the U.S. by Myriad and the other institutions in 1995.[37] Myriad is the exclusive licensee of these patents and has enforced them in the US against clinical diagnostic labs.[41] 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;[40] 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.[41][115] The patents begin to expire in 2014.

Peter Meldrum, CEO of Myriad Genetics, has acknowledged that Myriad has "other competitive advantages that may make such [patent] enforcement unnecessary" in Europe.[116]

Legal decisions surrounding the BRCA1 and BRCA2 patents will affect the field of genetic testing in general.[117] In June 2013, in Association for Molecular Pathology v. Myriad Genetics (No. 12-398), the US Supreme Court unanimously ruled that, "A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated," invalidating Myriad's patents on the BRCA1 and 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.[118] The Federal Court of Australia came to the opposite conclusion, upholding the validity of an Australian Myriad Genetics patent over the BRCA1 gene in February 2013,[119] but this decision is being appealed and the appeal will include consideration of the US Supreme Court ruling.[120]

References

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  32. ↑ High-Impact Science: Tracking down the BRCA genes (Part 2) - Cancer Research UK science blog, 2012
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  34. ↑ "A revolution at 50; kenneth offit". The New York Times. 2003-02-25. ISSN 0362-4331. https://www.nytimes.com/2003/02/25/science/a-revolution-at-50-kenneth-offit.html. 
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  39. ↑ Tavtigian SV, Kamb A, Simard J, Couch F, Rommens JM, Weber BL, "Chromosome 13-linked breast cancer susceptibility gene", US patent 5837492, issued 1998-11-17, assigned to Myriad Genetics, Inc., Endo Recherche, Inc., HSC Research & Development Limited Partnership, Trustees of the University of Pennsylvania
  40. ↑ 40.0 40.1 Myriad Investor Page—see "Myriad at a glance" accessed October 2012
  41. ↑ 41.0 41.1 41.2 Schwartz J (2009-05-12). "Cancer Patients Challenge the Patenting of a Gene". Health. New York Times. https://www.nytimes.com/2009/05/13/health/13patent.html. 
  42. ↑ 42.0 42.1 "The "portrait" of hereditary breast cancer". Breast Cancer Research and Treatment 89 (3): 297–304. 2005. doi:10.1007/s10549-004-2172-4. PMID 15754129. 
  43. ↑ 43.0 43.1 "A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes". Nature Genetics 13 (1): 117–119. 1996. doi:10.1038/ng0596-117. PMID 8673089. 
  44. ↑ 44.0 44.1 "Study of a single BRCA2 mutation with high carrier frequency in a small population". American Journal of Human Genetics 60 (5): 1079–1085. 1997. PMID 9150155. 
  45. ↑ "Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion.". Human Mutation 15 (1): 7–12. 2000. doi:10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N. PMID 10612815. 
  46. ↑ "Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer". Nature Genetics 13 (1): 126–128. 1996. doi:10.1038/ng0596-126. PMID 8673092. 
  47. ↑ "Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families". European Journal of Cancer 37 (16): 2082–2090. 2001. doi:10.1016/S0959-8049(01)00244-1. PMID 11597388. 
  48. ↑ "Evidence of founder mutations in Finnish BRCA1 and BRCA2 families". American Journal of Human Genetics 62 (6): 1544–1548. 1998. doi:10.1086/301880. PMID 9585608. 
  49. ↑ "Involvement of BRCA1 and BRCA2 in breast cancer in a western Finnish sub-population". Genetic Epidemiology 20 (2): 239–246. 2001. doi:10.1002/1098-2272(200102)20:2<239::AID-GEPI6>3.0.CO;2-Y. PMID 11180449. 
  50. ↑ "Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history". Clinical Genetics 55 (5): 318–324. 1999. doi:10.1034/j.1399-0004.1999.550504.x. PMID 10422801. 
  51. ↑ "Haplotype analysis suggests common founders in carriers of recurrent BRCA2 mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families". BMC Medical Genetics 7 (23): 23. 2006. doi:10.1186/1471-2350-7-23. PMID 16539696. 
  52. ↑ "The limited spectrum of pathogenic BRCA1 and BRCA2 mutations in the French Canadian breast and breast-ovarian cancer families, a founder population of Quebec, Canada". Bull Cancer 93 (9): 841–846. 2006. PMID 16980226. 
  53. ↑ "Prevalence of founder BRCA1 and BRCA2 mutations among breast and ovarian cancer patients in Hungary". International Journal of Cancer 86 (5): 737–740. 2000. doi:10.1002/(SICI)1097-0215(20000601)86:5<737::AID-IJC21>3.0.CO;2-1. PMID 10797299. 
  54. ↑ "Identification of a founder BRCA2 mutation in Sardinia". British Journal of Cancer 82 (3): 553–559. 2000. doi:10.1054/bjoc.1999.0963. PMID 10682665. 
  55. ↑ 55.0 55.1 Scottish/Northern Irish BRCAI/BRCA2 Consortium (2003). "BRCA1 and BRCA2 mutations in Scotland and Northern Ireland". British Journal of Cancer 88 (8): 1256–1262. doi:10.1038/sj.bjc.6600840. PMID 12698193. 
  56. ↑ "Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan". American Journal of Human Genetics 71 (3): 595–606. 2002. doi:10.1086/342506. PMID 12181777. 
  57. ↑ "BRCA2 founder mutation in Slovenian breast cancer families". European Journal of Human Genetics 10 (12): 879–882. 2002. doi:10.1038/sj.ejhg.5200886. PMID 12461697. 
  58. ↑ "Molecular analysis of the BRCA2 gene in 16 breast/ovarian cancer Spanish families". Clin. Genet. 54 (2): 142–7. 1998. doi:10.1111/j.1399-0004.1998.tb03717.x. PMID 9761393. 
  59. ↑ "Founder populations and their uses for breast cancer genetics". Cancer Research 2 (2): 77–81. 2000. doi:10.1186/bcr36. PMID 11250694. 
  60. ↑ 60.0 60.1 "BRCA2 is a mediator of RAD51- and DMC1-facilitated homologous recombination in Arabidopsis thaliana". New Phytol. 193 (2): 364–75. 2012. doi:10.1111/j.1469-8137.2011.03947.x. PMID 22077663. 
  61. ↑ "BRCA2 homolog required for proficiency in DNA repair, recombination, and genome stability in Ustilago maydis". Mol. Cell 10 (3): 683–91. 2002. doi:10.1016/s1097-2765(02)00632-9. PMID 12408834. 
  62. ↑ "Essential role of brc-2 in chromosome integrity of germ cells in C. elegans". Mol. Cells 26 (6): 590–4. 2008. PMID 18779660. 
  63. ↑ "RAD-51-dependent and -independent roles of a Caenorhabditis elegans BRCA2-related protein during DNA double-strand break repair". Mol. Cell. Biol. 25 (8): 3127–39. 2005. doi:10.1128/MCB.25.8.3127-3139.2005. PMID 15798199. 
  64. ↑ "Drosophila brca2 is required for mitotic and meiotic DNA repair and efficient activation of the meiotic recombination checkpoint". PLOS Genet. 4 (2): e31. 2008. doi:10.1371/journal.pgen.0040031. PMID 18266476. 
  65. ↑ "Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation". Nat. Genet. 17 (4): 423–30. 1997. doi:10.1038/ng1297-423. PMID 9398843. 
  66. ↑ "Characterizing a rat Brca2 knockout model". Oncogene 26 (11): 1626–35. 2007. doi:10.1038/sj.onc.1209960. PMID 16964288. 
  67. ↑ 67.0 67.1 "BRCA2 regulates DMC1-mediated recombination through the BRC repeats". Proc. Natl. Acad. Sci. U.S.A. 113 (13): 3515–20. 2016. doi:10.1073/pnas.1601691113. PMID 26976601. Bibcode: 2016PNAS..113.3515M. 
  68. ↑ 68.0 68.1 "BRCA2 is required for neurogenesis and suppression of medulloblastoma". EMBO J. 26 (11): 2732–42. 2007. doi:10.1038/sj.emboj.7601703. PMID 17476307. 
  69. ↑ "Low incidence of BRCA2 mutations in breast carcinoma and other cancers". Nat. Genet. 13 (2): 241–4. 1996. doi:10.1038/ng0696-241. PMID 8640236. 
  70. ↑ "Mutation analysis in the BRCA2 gene in primary breast cancers". Nat. Genet. 13 (2): 245–7. 1996. doi:10.1038/ng0696-245. PMID 8640237. 
  71. ↑ "BRCA2 mutations in primary breast and ovarian cancers". Nat. Genet. 13 (2): 238–40. 1996. doi:10.1038/ng0696-238. PMID 8640235. 
  72. ↑ 72.0 72.1 "Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer". Clin. Cancer Res. 13 (3): 832–8. 2007. doi:10.1158/1078-0432.CCR-05-2694. PMID 17289874. 
  73. ↑ 73.0 73.1 "Epigenetic factors controlling the BRCA1 and BRCA2 genes in sporadic ovarian cancer". Cancer Res. 62 (14): 4151–6. 2002. PMID 12124354. 
  74. ↑ "The BRCA1/2-directed miRNA signature predicts a good prognosis in ovarian cancer patients with wild-type BRCA1/2". Oncotarget 6 (4): 2397–406. 2015. doi:10.18632/oncotarget.2963. PMID 25537514. 
  75. ↑ 75.0 75.1 "Unraveling the mechanism of BRCA2 in homologous recombination". Nat. Struct. Mol. Biol. 18 (7): 748–54. 2011. doi:10.1038/nsmb.2096. PMID 21731065. 
  76. ↑ 76.0 76.1 76.2 "Overexpression of BRCA2 gene in sporadic breast tumours". Oncogene 18 (37): 5232–8. 1999. doi:10.1038/sj.onc.1202903. PMID 10498873. 
  77. ↑ 77.0 77.1 77.2 "Expression of BRCA1 and BRCA2 proteins and their correlation with clinical staging in breast cancer". J Cancer Res Ther 11 (1): 158–63. 2015. doi:10.4103/0973-1482.140985. PMID 25879355. 
  78. ↑ 78.0 78.1 "High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients". Int. J. Cancer 98 (6): 879–82. 2002. doi:10.1002/ijc.10231. PMID 11948466. 
  79. ↑ 79.0 79.1 "Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas". Mol. Cancer 8 (1): 48. 2009. doi:10.1186/1476-4598-8-48. PMID 19602291. 
  80. ↑ "Increased ID4 expression, accompanied by mutant p53 accumulation and loss of BRCA1/2 proteins in triple-negative breast cancer, adversely affects survival". Histopathology 68 (5): 702–12. 2016. doi:10.1111/his.12801. PMID 26259780. 
  81. ↑ 81.0 81.1 81.2 81.3 81.4 81.5 "Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair". Mol. Cell 12 (5): 1087–99. November 2003. doi:10.1016/S1097-2765(03)00424-6. PMID 14636569. 
  82. ↑ "Distinct roles of BARD1 isoforms in mitosis: full-length BARD1 mediates Aurora B degradation, cancer-associated BARD1beta scaffolds Aurora B and BRCA2". Cancer Res. 69 (3): 1125–34. February 2009. doi:10.1158/0008-5472.CAN-08-2134. PMID 19176389. 
  83. ↑ 83.0 83.1 "Inhibition of breast and brain cancer cell growth by BCCIPalpha, an evolutionarily conserved nuclear protein that interacts with BRCA2". Oncogene 20 (3): 336–45. January 2001. doi:10.1038/sj.onc.1204098. PMID 11313963. 
  84. ↑ 84.0 84.1 "Analysis of murine Brca2 reveals conservation of protein-protein interactions but differences in nuclear localization signals". J. Biol. Chem. 276 (40): 37640–8. October 2001. doi:10.1074/jbc.M106281200. PMID 11477095. 
  85. ↑ 85.0 85.1 "Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells". Mol. Cell 2 (3): 317–28. September 1998. doi:10.1016/S1097-2765(00)80276-2. PMID 9774970. 
  86. ↑ "Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport". Exp. Cell Res. 289 (2): 211–21. October 2003. doi:10.1016/S0014-4827(03)00261-1. PMID 14499622. 
  87. ↑ "Potential role of BRCA2 in a mitotic checkpoint after phosphorylation by hBUBR1". Cancer Res. 60 (6): 1531–5. March 2000. PMID 10749118. 
  88. ↑ "CBP-mediated post-translational N-glycosylation of BRCA2". Int J Oncol 35 (2): 16387–91. August 2009. doi:10.3892/ijo_00000351. PMID 19578754. 
  89. ↑ "EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer". Cell 115 (5): 523–35. November 2003. doi:10.1016/S0092-8674(03)00930-9. PMID 14651845. 
  90. ↑ "Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin". Mol. Cell. Biol. 24 (13): 5850–62. July 2004. doi:10.1128/MCB.24.13.5850-5862.2004. PMID 15199141. 
  91. ↑ "Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways". Hum. Mol. Genet. 13 (12): 1241–8. June 2004. doi:10.1093/hmg/ddh135. PMID 15115758. 
  92. ↑ "Tip60 is required for DNA interstrand cross-link repair in the Fanconi anemia pathway". J. Biol. Chem. 283 (15): 9844–51. April 2008. doi:10.1074/jbc.M709076200. PMID 18263878. 
  93. ↑ "Direct interaction of the Fanconi anaemia protein FANCG with BRCA2/FANCD1". Hum. Mol. Genet. 12 (19): 2503–10. October 2003. doi:10.1093/hmg/ddg266. PMID 12915460. 
  94. ↑ "Interaction with BRCA2 suggests a role for filamin-1 (hsFLNa) in DNA damage response". J. Biol. Chem. 276 (51): 48318–24. December 2001. doi:10.1074/jbc.M102557200. PMID 11602572. 
  95. ↑ "A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression". Cell 104 (2): 247–57. January 2001. doi:10.1016/S0092-8674(01)00209-4. PMID 11207365. 
  96. ↑ "A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes". Proc. Natl. Acad. Sci. U.S.A. 99 (11): 7420–5. May 2002. doi:10.1073/pnas.112008599. PMID 12032298. Bibcode: 2002PNAS...99.7420H. 
  97. ↑ 97.0 97.1 97.2 "The BRCA2 gene product functionally interacts with p53 and RAD51". Proc. Natl. Acad. Sci. U.S.A. 95 (23): 13869–74. November 1998. doi:10.1073/pnas.95.23.13869. PMID 9811893. Bibcode: 1998PNAS...9513869M. 
  98. ↑ "Entrez Gene: PALB2 partner and localizer of BRCA2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=79728. 
  99. ↑ 99.0 99.1 99.2 "M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex". J. Biol. Chem. 278 (38): 35979–87. September 2003. doi:10.1074/jbc.M210659200. PMID 12815053. 
  100. ↑ "BRCA2 associates with acetyltransferase activity when bound to P/CAF". Oncogene 17 (19): 2531–4. November 1998. doi:10.1038/sj.onc.1202475. PMID 9824164. 
  101. ↑ "Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression". Oncogene 23 (4): 865–72. January 2004. doi:10.1038/sj.onc.1207223. PMID 14647413. 
  102. ↑ "Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2". Nature 386 (6627): 804–10. April 1997. doi:10.1038/386804a0. PMID 9126738. Bibcode: 1997Natur.386..804S. 
  103. ↑ "Dynamic control of Rad51 recombinase by self-association and interaction with BRCA2". Mol. Cell 12 (4): 1029–41. October 2003. doi:10.1016/S1097-2765(03)00394-0. PMID 14580352. 
  104. ↑ 104.0 104.1 "The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment". Proc. Natl. Acad. Sci. U.S.A. 95 (9): 5287–92. April 1998. doi:10.1073/pnas.95.9.5287. PMID 9560268. Bibcode: 1998PNAS...95.5287C. 
  105. ↑ 105.0 105.1 "RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2". J. Biol. Chem. 272 (51): 31941–4. December 1997. doi:10.1074/jbc.272.51.31941. PMID 9405383. 
  106. ↑ "Multiple possible sites of BRCA2 interacting with DNA repair protein RAD51". Genes Chromosomes Cancer 21 (3): 217–22. March 1998. doi:10.1002/(SICI)1098-2264(199803)21:3<217::AID-GCC5>3.0.CO;2-2. PMID 9523196. 
  107. ↑ "Insights into DNA recombination from the structure of a RAD51-BRCA2 complex". Nature 420 (6913): 287–93. November 2002. doi:10.1038/nature01230. PMID 12442171. Bibcode: 2002Natur.420..287P. 
  108. ↑ "RAD51 localization and activation following DNA damage". Philos. Trans. R. Soc. Lond. B Biol. Sci. 359 (1441): 87–93. January 2004. doi:10.1098/rstb.2003.1368. PMID 15065660. 
  109. ↑ "Interaction between BRCA2 and replication protein A is compromised by a cancer-predisposing mutation in BRCA2". Oncogene 22 (1): 28–33. January 2003. doi:10.1038/sj.onc.1206071. PMID 12527904. 
  110. ↑ "Interaction between the product of the breast cancer susceptibility gene BRCA2 and DSS1, a protein functionally conserved from yeast to mammals". Mol. Cell. Biol. 19 (7): 4633–42. July 1999. doi:10.1128/MCB.19.7.4633. PMID 10373512. 
  111. ↑ 111.0 111.1 111.2 111.3 111.4 "BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure". Science 297 (5588): 1837–48. September 2002. doi:10.1126/science.297.5588.1837. PMID 12228710. Bibcode: 2002Sci...297.1837Y. 
  112. ↑ "BRCA2 and Smad3 synergize in regulation of gene transcription". Oncogene 21 (36): 5660–4. August 2002. doi:10.1038/sj.onc.1205732. PMID 12165866. 
  113. ↑ "Internal repeats in the BRCA2 protein sequence". Nat. Genet. 13 (1): 22–3. May 1996. doi:10.1038/ng0596-22. PMID 8673099. 
  114. ↑ Alagar, S.; Bahadur, R. P. (2020). "DSS1 allosterically regulates the conformation of the tower domain of BRCA2 that has dsDNA binding specificity for homologous recombination". International Journal of Biological Macromolecules 165 (Pt A): 918–929. doi:10.1016/j.ijbiomac.2020.09.230. PMID 33011260. 
  115. ↑ "How Will Myriad Respond to the Next Generation of BRCA Testing?". Robinson, Bradshaw, and Hinson. 2011-03-01. http://www.genomicslawreport.com/index.php/2011/03/01/how-will-myriad-respond-to-the-next-generation-of-brca-testing/. 
  116. ↑ "Genetics and Patenting". Human Genome Project Information. U.S. Department of Energy Genome Programs. 2010-07-07. http://www.ornl.gov/sci/techresources/Human_Genome/elsi/patents.shtml. 
  117. ↑ "Supreme Court Rules Human Genes May Not Be Patented". New York Times. 13 June 2013. https://www.nytimes.com/2013/06/14/us/supreme-court-rules-human-genes-may-not-be-patented.html?_r=0. 
  118. ↑ "Landmark patent ruling over breast cancer gene BRCA1". Sydney Morning Herald. February 15, 2013. http://www.smh.com.au/national/health/landmark-patent-ruling-over-breast-cancer-gene-brca1-20130215-2egsq.html. 
  119. ↑ "Companies can't patent genes, US court rules". Sydney Morning Herald. June 14, 2013. http://www.smh.com.au/technology/sci-tech/companies-cant-patent-genes-us-court-rules-20130614-2o836.html. 

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