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BRCA2

From Wikipedia, the free encyclopedia
BRCA2
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesBRCA2,BRCC2, BROVCA2, FACD, FAD, FAD1, FANCD, FANCD1, GLM3, PNCA2, XRCC11, breast cancer 2, DNA repair associated, breast cancer 2, early onset, BRCA2 DNA repair associated, Genes
External IDsOMIM:600185;MGI:109337;HomoloGene:41;GeneCards:BRCA2;OMA:BRCA2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

675

12190

Ensembl

ENSG00000139618

ENSMUSG00000041147

UniProt

P51587

P97929

RefSeq (mRNA)

NM_000059

NM_001081001
NM_009765

RefSeq (protein)

NP_000050

NP_001074470
NP_033895

Location (UCSC)Chr 13: 32.32 – 32.4 MbChr 5: 150.45 – 150.49 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

BRCA2andBRCA2(/ˌbrækəˈtuː/[5]) are humangenesand theirproteinproducts, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originallybreast cancer 2;currentlyBRCA2, DNA repair associated) aremaintainedby theHUGO Gene Nomenclature Committee.One alternative symbol,FANCD1,recognizes its association with theFANC proteincomplex.Orthologs,styledBrca2and Brca2, are common in othervertebratespecies.[6][7]BRCA2is a humantumor suppressor gene[8][9](specifically, acaretaker gene), found in all humans; itsprotein,also called by thesynonymbreast cancer type 2 susceptibility protein,is responsible for repairing DNA.[10]

BRCA2andBRCA1are normally expressed in the cells ofbreastand other tissue, where they help repair damagedDNAor destroy cells if DNA cannot be repaired. They are involved in the repair ofchromosomaldamage with an important role in the error-freerepair of DNAdouble strand breaks.[11][12]IfBRCA1orBRCA2itself is damaged by aBRCAmutation,damaged DNA is not repaired properly, and this increases the risk forbreast cancer.[13][14]BRCA1andBRCA2have been described as "breast cancer susceptibility genes" and "breast cancer susceptibility proteins". The predominant allele has a normal tumor suppressive function whereas highpenetrancemutations in these genes cause a loss of tumor suppressive function, which correlates with an increased risk of breast cancer.[15]

TheBRCA2gene is located on the long (q) arm ofchromosome 13at position 12.3 (13q12.3).[16]The human referenceBRCA2gene contains 27 exons, and the cDNA has 10,254 base pairs[17]coding for a protein of 3418 amino acids.[18][19]

Function[edit]

Recombinational repair of DNA double-strand damage - some key steps.ATM(ATM) is aprotein kinasethat is recruited and activated byDNA double-strand breaks.DNA double-strand damages also activate theFanconi anemia core complex(FANCA/B/C/E/F/G/L/M).[20]The FA core complexmonoubiquitinatesthe downstream targets FANCD2 and FANCI.[21]ATM activates (phosphorylates)CHEK2andFANCD2[22]CHEK2 phosphorylates BRCA1.[23]Ubiquinated FANCD2 complexes withBRCA1andRAD51.[24]ThePALB2protein acts as a hub,[25]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 complexRAD51B-RAD51C-RAD51D-XRCC2(BCDX2). The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites.[26]RAD51plays a major role inhomologous recombinationalrepair 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 theBRCA1andBRCA2genes are very different, at least some functions are interrelated. Theproteinsmade by bothgenesare essential for repairing damaged DNA (see Figure of recombinational repair steps). BRCA2 binds the single strand DNA and directly interacts with the recombinaseRAD51to stimulate[27]and maintain[28]strand invasion, a vital step ofhomologous 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)[29]can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion.[30]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 thehuman genomeand prevent dangerous gene rearrangements that can lead to hematologic and other cancers.

BRCA2 has been shown to possess a crucial role in protection from theMRE11-dependent nucleolytic degradation of thereversed forksthat are forming duringDNA replicationfork stalling (caused by obstacles such as mutations, intercalating agents etc.).[31]

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

Clinical significance[edit]

Absolute risk of cancers inBRCA1or BRCA2 mutation.[32]
Further information:BRCA mutation

Certain variations of theBRCA2gene increase risks forbreast canceras part of ahereditary breast–ovarian cancer syndrome.Researchers have identified hundreds of mutations in theBRCA2gene, many of which cause an increased risk of cancer.BRCA2mutations 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 theBRCA2gene is abnormal, and does not function properly. Researchers believe that the defectiveBRCA2protein is unable to fix DNA damage that occurs throughout the genome. As a result, there is an increase in mutations due to error-pronetranslesion synthesispast 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 theBRCA2gene have one type ofFanconi 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 ofleukemia(a type of blood cell cancer); solid tumors, particularly of the head, neck, skin, and reproductive organs; andbone marrow suppression(reduced blood cell production that leads toanemia). Women having inherited a defectiveBRCA1orBRCA2gene have risks for breast and ovarian cancer that are so high and seem so selective that many mutation carriers choose to haveprophylactic surgery.There has been much conjecture to explain such apparently striking tissue specificity. Major determinants of whereBRCA1- andBRCA2-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 beyondBRCA1orBRCA2.A major advantage of this model is that it suggests there are some options in addition to prophylactic surgery.[33]

In addition to breast cancer in men and women, mutations inBRCA2also lead to an increased risk ofovarian,uterine tube,prostateandpancreatic cancer.In some studies, mutations in the central part of the gene have been associated with a higher risk ofovarian cancerand a lower risk ofprostate cancerthan mutations in other parts of the gene. Several other types of cancer[which?]have also been seen in certain families withBRCA2mutations.[citation needed]

In general, strongly inherited gene mutations (including mutations inBRCA2) account for only 5-10% of breast cancer cases; the specific risk of getting breast or other cancer for anyone carrying aBRCA2mutation depends on many factors.[34]

History[edit]

The BRCA2 gene was discovered in 1994.[35][16][36]In 1996,Kenneth Offitand his research group atMemorial Sloan Kettering Cancer Centersuccessfully identified the most common mutation on the gene associated with breast and ovarian cancer among individuals ofAshkenazi Jewishancestry.[37][38][39][40]

The gene was first cloned by scientists atMyriad Genetics,Endo Recherche, Inc., HSC Research & Development Limited Partnership, and theUniversity of Pennsylvania.[41]

Methods to diagnose the likelihood of a patient with mutations inBRCA1andBRCA2getting cancer were covered bypatentsowned or controlled byMyriad Genetics.[42][43]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;[44]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 landmarkAssociation for Molecular Pathology v. Myriad Geneticslawsuit.[45]

Germline mutations and founder effect[edit]

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.[46]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.[47][48]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 adynamic listand may never be able to satisfy particular standards for completeness. You can help byadding missing itemswithreliable sources.
Population or subgroup BRCA2 mutation(s)[46][49] Reference(s)
Ashkenazi Jewish 6174delT [50]
Dutch 5579insA [51]
Finns 8555T>G, 999del5, IVS23-2A>G [52][53]
French Canadians 8765delAG, 3398delAAAAG [54][55][56]
Hungarians 9326insA [57]
Icelanders 999del5 [47][48]
Italians 8765delAG [58]
Northern Irish 6503delTT [59]
Pakistanis 3337C>T [60]
Scottish 6503delTT [59]
Slovenians IVS16-2A>G [61]
Spanish 3034delAAAC(codon936), 9254del5 [62]
Swedish 4486delG [63]

Meiosis[edit]

In the plantArabidopsis thaliana,loss of theBRCA2homologAtBRCA2causes severe defects in both malemeiosisand in the development of the femalegametocyte.[64]AtBRCA2 protein is required for proper localization of thesynaptonemal complexprotein 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 meiotichomologous recombinationalrepair of DNA damages.[64]

Homologs of BRCA2 are also essential for meiosis in the fungusUstilago maydis,[65]the wormCaenorhabditis elegans,[66][67]and the fruitflyDrosophila melanogaster.[68]

Mice that produce truncated versions of BRCA2 are viable but sterile.[69]BRCA2 mutant rats have a phenotype of growth inhibition and sterility in both sexes.[70]Aspermatogenesis in these mutant rats is due to a failure of homologous chromosome synapsis during meiosis.

BRC repeat sequences[edit]

DMC1(DNA meiotic recombinase 1) is ameiosisspecific homolog ofRAD51that mediates strand exchange duringhomologous recombinationalrepair. 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.[71]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.[71]The ssDNA complexed with DMC1 can pair with homologous ssDNA from another chromosome during the synopsis stage ofmeiosisto form a joint molecule, a central step inhomologous 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[edit]

BRCA2 is required in the mouse forneurogenesisand suppression ofmedulloblastoma.[72]‘’BRCA2’’ loss profoundly affects neurogenesis, particularly during embryonic and postnatal neural development. These neurological defects arise from DNA damage.[72]

Epigenetic control[edit]

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.[73][74][75]

In non-small cell lung cancer, BRCA2 is epigenetically repressed by hypermethylation of the promoter.[76]In this case, promoter hypermethylation is significantly associated with lowmRNAexpression 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.[77]This indicates that hypomethylation of the BRCA2 promoter and5'-UTR regionsleads to over-expression of BRCA2 mRNA.

One report indicated some epigenetic control of BRCA2 expression by themicroRNAsmiR-146a and miR-148a.[78]

BRCA2 expression in cancer[edit]

Ineukaryotes,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.[79]BRCA2 also redirects RAD51 from double-stranded DNA and prevents dissociation from ssDNA.[79]In addition, the fourparalogsofRAD51,consisting of RAD51B (RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3),XRCC2form a complex called the BCDX2 complex (see Figure: Recombinational repair of DNA). This complex participates in RAD51 recruitment or stabilization at damage sites.[26]The BCDX2 complex appears to act by facilitating the assembly or stability of theRAD51 nucleoprotein filament.RAD51 catalyses strand transfer between a broken sequence and its undamaged homologue to allow re-synthesis of the damaged region (seehomologous recombination models).

Some studies of cancers report over-expressedBRCA2whereas other studies report under-expression ofBRCA2.At least two reports found over-expression in some sporadic breast tumors and under-expression in other sporadic breast tumors.[80][81](see Table).

Many cancers have epigenetic deficiencies in various DNA repair genes (seeFrequencies of epimutations in DNA repair genes in cancers). These repair deficiencies likely cause increased unrepaired DNA damages. The over-expression ofBRCA2seen in many cancers may reflect compensatoryBRCA2over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages. Egawa et al.[82]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 ofBRCA2would itself lead to increased unrepaired DNA damages. Replication errors past these damages (seetranslesion synthesis) would lead to increased mutations and cancer.

BRCA2expression in sporadic cancers
Cancer Over or Under expression Frequency of altered expression Evaluation method Ref.
Sporadic ovarian cancer Over-expression 80% messenger RNA [77]
Sporadic ovarian cancer Under-expression 42% immunohistochemistry [83]
(recurrent cancer in study above) Increased-expression 71% immunohistochemistry [83]
Non-small cell lung cancer Under-expression 34% immunohistochemistry [76]
Breast cancer Over-expression 66% messenger RNA [82]
Breast cancer Over-expression 20% messenger RNA [80]
(same study as above) Under-expression 11% messenger RNA [80]
Breast cancer Over-expression 30% immunohistochemistry [81]
(same study as above) Under-expression 30% immunohistochemistry [81]
Triple negative breast cancer Under-expression 90% immunohistochemistry [84]

Interactions[edit]

BRCA2 has been shown tointeractwith

Domain architecture[edit]

BRCA2 repeat
crystal structure of a rad51-brca2 brc repeat complex
Identifiers
SymbolBRCA2
PfamPF00634
InterProIPR002093
SCOP21n0w/SCOPe/SUPFAM
Available protein structures:
Pfam structures/ECOD
PDBRCSB PDB;PDBe;PDBj
PDBsumstructure summary

BRCA2 contains a number of 39amino acidrepeatsthat are critical for binding toRAD51(a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment.[101][108][109][117]

The BRCA2 helical domain adopts ahelicalstructure, 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 shorthelices(alpha 2 to alpha 4), meanders around the surface of the corestructure.In BRCA2, the alpha 9 and alpha 10 helices pack with the BRCA2 OB1 domain throughvan der Waalscontacts involvinghydrophobicand aromatic residues, and also throughside-chainand backbonehydrogen bonds.This domainbindsthe 70-amino acidDSS1(deleted in split-hand/split foot syndrome) protein, which was originally identified as one of threegenesthat map to a 1.5-Mblocusdeletedin an inherited developmental malformation syndrome.[115]

The BRCA OB1 domain assumes an OB fold, which consists of a highly curved five-strandedbeta-sheetthat closes on itself to form abeta-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 DNAbinding.The domain alsobindsthe 70-amino acidDSS1(deleted in split-hand/split foot syndrome) protein.[115]

The BRCA OB3 domain assumes an OB fold, which consists of a highly curved five-strandedbeta-sheetthat closes on itself to form abeta-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 strongssDNAbinding.[115]

The Tower domain adopts asecondary structureconsisting of a pair of long,antiparallelalpha-helices(the stem) that support a three-helix bundle (3HB) at their end. The 3HB contains ahelix-turn-helixmotif and is similar to the DNAbindingdomainsof thebacterialsite-specificrecombinases,and ofeukaryoticMybandhomeodomaintranscription factors.The Tower domain has an important role in thetumour suppressorfunction of BRCA2, and is essential for appropriate binding of BRCA2 to DNA.[115]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.[118]

Patents, enforcement, litigation, and controversy[edit]

Main article:Association for Molecular Pathology v. Myriad Genetics

A patent application for the isolatedBRCA1gene 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) andMyriad Geneticsin 1994;[42]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.[41]Myriad is the exclusive licensee of thesepatentsand has enforced them in the US against clinical diagnostic labs.[45]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;[44]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 landmarkAssociation for Molecular Pathology v. Myriad Geneticslawsuit.[45][119]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.[120]

Legal decisions surrounding the BRCA1 and BRCA2 patents will affect the field ofgenetic testingin general.[121]In June 2013, inAssociation for Molecular Pathology v. Myriad Genetics(No. 12-398), theUS Supreme Courtunanimously 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.[122]TheFederal Court of Australiacame to the opposite conclusion, upholding the validity of an Australian Myriad Genetics patent over the BRCA1 gene in February 2013,[123]but this decision is being appealed and the appeal will include consideration of the US Supreme Court ruling.[124]

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