BRCA2

Breast cancer 2, early onset
PDB rendering based on 1n0w.
Available structures PDB 1N0W, 3EU7
Identifiers
Symbols	BRCA2; BRCC2; BROVCA2; FACD; FAD; FAD1; FANCB; FANCD; FANCD1; GLM3; PNCA2
External IDs	OMIM: 600185 MGI: 109337 HomoloGene: 41 GeneCards: BRCA2 Gene
Gene Ontology Molecular function • protease binding • DNA binding • single-stranded DNA binding • histone acetyltransferase activity • protein binding • H3 histone acetyltransferase activity • H4 histone acetyltransferase activity • gamma-tubulin binding Cellular component • nucleus • nucleoplasm • nucleolus • cytoplasm • centrosome • stored secretory granule • BRCA2-MAGE-D1 complex • protein complex Biological process • double-strand break repair via homologous recombination • double-strand break repair via homologous recombination • oocyte maturation • inner cell mass cell proliferation • DNA repair • nucleotide-excision repair • double-strand break repair • double-strand break repair • DNA recombination • DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator • cell cycle • regulation of S phase of mitotic cell cycle • male meiosis I • spermatogenesis • brain development • cell aging • response to nutrient • female gonad development • response to X-ray • response to UV-C • response to gamma radiation • hemopoiesis • mammary gland development • homologous chromosome orientation involved in meiotic metaphase I plate congression • regulation of cytokinesis • cell cycle cytokinesis • negative regulation of mammary gland epithelial cell proliferation • multicellular organism growth • DNA damage response, signal transduction by p53 class mediator resulting in induction of apoptosis • chordate embryonic development • response to estrogen stimulus • histone H3 acetylation • histone H4 acetylation • positive regulation of transcription, DNA-dependent • positive regulation of mitotic cell cycle • replication fork protection • chromosome organization • centrosome duplication Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	675	12190
Ensembl	ENSG00000139618	ENSMUSG00000041147
UniProt	P51587	Q3TN53
RefSeq (mRNA)	NM_000059.3	NM_001081001
RefSeq (protein)	NP_000050.2	NP_001074470
Location (UCSC)	Chr 13: 32.89 – 32.97 Mb	Chr 5: 151.33 – 151.37 Mb
PubMed search	[2]	[3]

BRCA2 repeat
crystal structure of a rad51-brca2 brc repeat complex
Identifiers
Symbol	BRCA2
Pfam	PF00634
InterPro	IPR002093
SCOP	1n0w
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

BRCA-2 helical
structure of a brca2-dss1 complex
Identifiers
Symbol	BRCA-2_helical
Pfam	PF09169
InterPro	IPR015252
SCOP	1iyj
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

BRCA2, oligonucleotide/oligosaccharide-binding, domain 1
structure of a brca2-dss1 complex
Identifiers
Symbol	BRCA-2_OB1
Pfam	PF09103
InterPro	IPR015187
SCOP	1iyj
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

BRCA2, oligonucleotide/oligosaccharide-binding, domain 3
structure of a brca2-dss1 complex
Identifiers
Symbol	BRCA-2_OB3
Pfam	PF09104
InterPro	IPR015188
SCOP	1iyj
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

Tower domain
structure of a brca2-dss1 complex
Identifiers
Symbol	Tower
Pfam	PF09121
InterPro	IPR015205
SCOP	1mje
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

BRCA2 (Breast Cancer 2 susceptibility protein) is a protein that in humans is encoded by the BRCA2 gene.^[1] BRCA2 orthologs have been identified in most mammals for which complete genome data are available.^[2] BRCA2 belongs to the tumor suppressor gene family^[3][4] and the protein encoded by this gene is involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double strand breaks.^[5]

The BRCA2 gene is located on the long (q) arm of chromosome 13 at position 12.3 (13q12.3) and is 84,188 base pairs long.^[1]

Contents 1 Function 2 Clinical significance 3 History 4 Germ line BRCA2 mutations and founder effect 5 Interactions 6 Domain architecture 7 See also 8 References 9 Further reading 10 External links

Function

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. The BRCA2 protein binds to and regulates the protein produced by the RAD51 gene to fix breaks in DNA. 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). By repairing DNA, these three proteins play a role in maintaining the stability of the human genome and prevent dangerous gene rearrangements that can lead to hematologic cancers.^[5]

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

Clinical significance

Certain variations of the BRCA2 gene cause an increased risk 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 (the building material of chromosomes) 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 help fix mutations that occur in other genes. As a result, mutations build up and 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). A pathogenic mutation almost anywhere in a model pathway for DNA double strand break repair containing BRCA1 and BRCA2 greatly increases the risks for a subgroup of lymphomas and leukemia.^[5]

In addition to breast cancer in men and women, mutations in BRCA2 also lead to an increased risk of ovarian, Fallopian tube, prostate, and pancreatic cancers, as well as malignant melanoma. 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.

History

The BRCA2 gene was discovered in 1994 by Professor Michael Stratton and Dr Richard Wooster (Institute of Cancer Research, UK).^[1] The Wellcome Trust Sanger Institute (Hinxton, Cambs, UK) collaborated with Stratton and Wooster to isolate the gene. In honour of this discovery and collaboration, the Wellcome Trust has participated in the construction of a cycle path between Addenbrooke's Hospital site in Cambridge and the nearby village of Great Shelford. It is decorated with over 10,000 lines of 4 colours representing the nucleotide sequence of BRCA2. It makes up part of National Cycle Route 11, and can be seen from trains running between Cambridge and London.

Germ line BRCA2 mutations and founder effect

All germ line 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.^[6] 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.^[7][8] 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 an incomplete list, which 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)[6][9]	Reference(s)
Ashkenazi Jewish	6174delT	[10]
Dutch	5579insA	[11]
Finns	8555T>G, 999del5, IVS23-2A>G	[12][13]
French Canadians	8765delAG	[14]
Germans
Hungarians	9326insA	[15]
Icelandics	999del5	[7][8]
Italians	8765delAG	[16]
Northern Irish	6503delTT	[17]
Pakistanis	3337C>T	[18]
Scottish	6503delTT	[17]
Slovenians	IVS16-2A>G	[19]
Spanish	3034delAAAC(codon936), 9254del5	[20]
Swedish	4486delG	[21]

Interactions

BRCA2 has been shown to interact with

Domain architecture

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.^{[38][44][45][53]}

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.^[51]

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.^[51]

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.^[51]

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.^[51]

See also

• BRCA1
• DNA repair
• PALB2

References

Further reading

External links

• MeSH BRCA2 Protein
• GeneReviews/NCBI/NIH/UW entry on BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
• OMIM entries on BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
• EntrezGene 675
• GeneCard
• Cancer.gov
• "FORCE: Facing Our Risk of Cancer Empowered -- Hereditary, Genetic Breast or Ovarian Cancer and BRCA Issues". Facing Our Risk of Cancer Empowered, Inc.. http://www.facingourrisk.org/. Retrieved 2008-10-11. 
• UCSC Genome Browser View
• Johan T. den Dunnen; Stylianos E. Antonarakis. "A mutation nomenclature for BRCA2 mutations". Wiley Interscience. http://www3.interscience.wiley.com/cgi-bin/fulltext/68503056/PDFSTART?CRETRY=1&SRETRY=0. Retrieved 2010-02-10. 
• UCSC Gene details page

PDB gallery 1n0w: Crystal structure of a RAD51-BRCA2 BRC repeat complex

Neoplasm: Tumor suppressor genes/proteins and Oncogenes/Proto-oncogenes Ligand Growth factors ONCO: c-Sis/PDGF · HGF Receptor Wnt signaling pathway TSP: CDH1 Hedgehog signaling pathway TSP: PTCH1 TGF beta signaling pathway TSP: TGF beta receptor 2 Receptor tyrosine kinase ONCO: ErbB/c-ErbB (HER2/neu, Her 3) - c-Met - c-Ret JAK-STAT signaling pathway ONCO: c-Kit - Flt3 Intracellular signaling P+Ps Wnt signaling pathway ONCO: Beta-catenin · TSP: APC TGF beta signaling pathway TSP: SMAD2, SMAD4 Akt/PKB signaling pathway TSP: PTEN · ONCO: c-Akt Hippo signaling pathway TSP: Neurofibromin 2/Merlin MAPK/ERK pathway TSP: Neurofibromin 1 · ONCO: c-Ras/HRAS, c-Raf Other/unknown TSP: Maspin · ONCO: c-Src Nucleus Cell cycle TSP: p53 · pRb · WT1 · p16/p14arf · ONCO: CDK4 · Cyclin D · Cyclin E DNA repair/Fanconi ONCO: BRCA1 - BRCA2 Ubiquitin ligase TSP: VHL  · ONCO: CBL - MDM2 Transcription factor TSP: KLF6  · ONCO: AP-1 (c-Fos, c-Jun) - c-Myc Mitochondria Apoptosis inhibitor: SDHB - SDHD Other/ungrouped c-Bcl-2 - Notch - Stathmin M: NEO tsoc, mrkr tumr, epon, para drug (L1i/1e/V03)

This article incorporates text from the public domain Pfam and InterPro IPR002093

This article incorporates text from the public domain Pfam and InterPro IPR015252

This article incorporates text from the public domain Pfam and InterPro IPR015187

This article incorporates text from the public domain Pfam and InterPro IPR015205