From Wikipedia, the free encyclopedia - View original article

Breast cancer 2, early onset

PDB rendering based on 1n0w.
Available structures
PDBOrtholog search: PDBe, RCSB
External IDsOMIM600185 MGI109337 HomoloGene41 GeneCards: BRCA2 Gene
RNA expression pattern
PBB GE BRCA2 208368 s at tn.png
More reference expression data
RefSeq (mRNA)NM_000059.3NM_001081001.1
RefSeq (protein)NP_000050.2NP_001074470.1
Location (UCSC)Chr 13:
32.89 – 32.97 Mb
Chr 5:
150.52 – 150.57 Mb
PubMed search[1][2]
Jump to: navigation, search
Breast cancer 2, early onset

PDB rendering based on 1n0w.
Available structures
PDBOrtholog search: PDBe, RCSB
External IDsOMIM600185 MGI109337 HomoloGene41 GeneCards: BRCA2 Gene
RNA expression pattern
PBB GE BRCA2 208368 s at tn.png
More reference expression data
RefSeq (mRNA)NM_000059.3NM_001081001.1
RefSeq (protein)NP_000050.2NP_001074470.1
Location (UCSC)Chr 13:
32.89 – 32.97 Mb
Chr 5:
150.52 – 150.57 Mb
PubMed search[1][2]
BRCA2 repeat
PDB 1n0w EBI.jpg
crystal structure of a rad51-brca2 brc repeat complex
BRCA-2 helical
PDB 1miu EBI.jpg
structure of a brca2-dss1 complex
BRCA2, oligonucleotide/oligosaccharide-binding, domain 1
PDB 1miu EBI.jpg
structure of a brca2-dss1 complex
BRCA2, oligonucleotide/oligosaccharide-binding, domain 3
PDB 1miu EBI.jpg
structure of a brca2-dss1 complex
Tower domain
PDB 1miu EBI.jpg
structure of a brca2-dss1 complex

BRCA2 (breast cancer type 2 susceptibility protein) is a protein found inside cells. In humans, the instructions to make this protein are carried by a gene, also called BRCA2.[1] BRCA2 belongs to the tumor suppressor gene family,[2][3] and orthologs have been identified in most mammals for which complete genome data are available.[4] 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).[1] The human reference BRCA 2 gene contains 27 exons, and the cDNA has 10,254 base pairs[6] coding for a protein of 3418 amino acids.[7][8]

The gene was first cloned by scientists at Myriad Genetics, Endo Recherche, Inc., HSC Research & Development Limited Partnership, and University of Pennsylvania.[9]

Methods to diagnose the likelihood of a patient with these mutations getting cancer were covered by patents owned or controlled by Myriad Genetics.[9][10] Myriad's business model of exclusively offering the diagnostic test 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;[11] 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.[12]



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. BRCA2 binds the single strand DNA and directly interacts with the recombinase RAD51 to stimulates strand invasion a vital step of homologous recombination. The localization of RAD51 to the DNA double-strand break requires the formation of BRCA1-PALB2-BRCA2 complex. PALB2 (Partner and localizer of BRCA2)[13] can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion.[14] 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.

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 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 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.

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.[15]


The BRCA2 gene was discovered in 1994 by Professor Michael Stratton and Dr Richard Wooster (Institute of Cancer Research, UK).[1][16] 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 participated in the construction of a cycle and foot path between the Addenbrooke's Hospital site in Cambridge and the nearby village of Great Shelford in 2005. The path by Cambridgeshire County Council and Sustrans is decorated with 10,257 stripes of 4 colours representing the nucleotide sequence of BRCA2 (green representing adenine, blue representing cytosine, yellow representing guanine, and red representing thymine).[17] It makes up part of National Cycle Route 11, and can be seen from trains running between Cambridge and London.

DNA cyclepath to Shelford - - 538440.jpg

The start of the cycle path

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.[18] 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.[19][20] 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.

Population or subgroupBRCA2 mutation(s)[18][21]Reference(s)
Ashkenazi Jewish6174delT[22]
Finns8555T>G, 999del5, IVS23-2A>G[24][25]
French Canadians8765delAG[26]
Northern Irish6503delTT[29]
Spanish3034delAAAC(codon936), 9254del5[32]


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.[50][57][58][66]

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.[64]

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.[64]

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.[64]

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.[64]

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;[10] 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.[9] Myriad is the exclusive licensee of these patents and has enforced them in the US against clinical diagnostic labs.[12] 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;[11] 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.[12][67] The patents begin 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-provide status."[68][69] Peter Meldrum, CEO of Myriad Genetics, has acknowledged that Myriad has "other competitive advantages that may make such [patent] enforcement unnecessary" in Europe.[70]

Legal decisions surrounding the BRCA1 and BRCA2 patents will effect the field of genetic testing in general.[71]

See also


  1. ^ a b c Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D, et al (September 1994). "Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13". Science 265 (5181): 2088–90. doi:10.1126/science.8091231. PMID 8091231.
  2. ^ Duncan JA, Reeves JR, Cooke TG (October 1998). "BRCA1 and BRCA2 proteins: roles in health and disease". Molecular pathology : MP 51 (5): 237–47. doi:10.1136/mp.51.5.237. PMC 395646. PMID 10193517. //
  3. ^ Yoshida K, Miki Y (November 2004). "Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage". Cancer science 95 (11): 866–71. doi:10.1111/j.1349-7006.2004.tb02195.x. PMID 15546503.
  4. ^ "OrthoMaM phylogenetic marker: BRCA2 coding sequence".
  5. ^ a b Friedenson B (2008-06-08). "Breast cancer genes protect against some leukemias and lymphomas" (video). SciVee.
  6. ^ "BRCA2 breast cancer 2, early onset [Homo sapiens"]. EntrezGene. National Center for Biotechnology Information, U.S. National Library of Medicine.
  7. ^ "Breast cancer type 2 susceptibility protein - Homo sapiens (Human)". P51587. UniProt.
  8. ^ Williams-Jones B (2002). Genetic testing for sale: Implications of commercial brca testing in Canada (Ph.D.). The University of British Columbia.
  9. ^ a b c US patent 5837492, Tavtigian SV, Kamb A, Simard J, Couch F, Rommens JM, Weber BL, "Chromosome 13-linked breast cancer susceptibility gene", issued 1998-11-17, assigned to Myriad Genetics, Inc., Endo Recherche, Inc., HSC Research & Development Limited Partnership, Trustees of the University of Pennsylvaina 
  10. ^ a b US patent 5747282, Skolnick HS, Goldgar DE, Miki Y, Swenson J, Kamb A, Harshman KD, Shattuck-Eidens DM, Tavtigian SV, Wiseman RW, Futreal PA, "7Q-linked breast and ovarian cancer susceptibility gene", issued 1998-05-05, assigned to Myraid Genetics, Inc., The United States of America as represented by the Secretary of Health and Human Services, and University of Utah Research Foundation 
  11. ^ a b Myriad Investor Page—see "Myriad at a glance" accessed October 2012
  12. ^ a b c Schwartz J (2009-05-12). "Cancer Patients Challenge the Patenting of a Gene". Health. New York Times.
  13. ^ a b Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM (June 2006). "Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2". Mol. Cell 22 (6): 719–29. doi:10.1016/j.molcel.2006.05.022. PMID 16793542.
  14. ^ Buisson R, Dion-Côté A.M, et al. (2010). "Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination.". Nature Structural & molecular biology 17 (10): 1247–54. doi:10.1038/nsmb.1915. PMID 20871615.
  15. ^ "High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes". National Cancer Institute. Retrieved 7 December 2012.
  16. ^ High-Impact Science: Tracking down the BRCA genes (Part 2) - Cancer Research UK science blog, 2012
  17. ^ Route information board
  18. ^ a b Lacroix M, Leclercq G (2005). "The "portrait" of hereditary breast cancer". Breast Cancer Research and Treatment 89 (3): 297–304. doi:10.1007/s10549-004-2172-4. PMID 15754129.
  19. ^ a b Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, Tavtigian SV, Tulinius H, Ogmundsdottir HM, Eyfjord JE (1996). "A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes". Nature Genetics 13 (1): 117–119. doi:10.1038/ng0596-117. PMID 8673089.
  20. ^ a b Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G, Jonasson JG, Tryggvadottir L, Tulinius H, Eyfjord JE (1997). "Study of a single BRCA2 mutation with high carrier frequency in a small population". American Journal of Human Genetics 60 (5): 1079–1085. PMC 1712443. PMID 9150155. //
  21. ^ den Dunnen JT, Antonarakis, SE. (2000). "Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion.". Human Mutation 15 (1): 7–12. doi:10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N. PMID 10612815.
  22. ^ Neuhausen S, Gilewski T, Norton L, Tran T, McGuire P, Swensen J, Hampel H, Borgen P, Brown K, Skolnick M, Shattuck-Eidens D, Jhanwar S, Goldgar D, Offit K (1996). "Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer". Nature Genetics 13 (1): 126–128. doi:10.1038/ng0596-126. PMID 8673092.
  23. ^ Verhoog LC, van den Ouweland AM, Berns E, van Veghel-Plandsoen MM, van Staveren IL, Wagner A, Bartels CC, Tilanus-Linthorst MM, Devilee P, Seynaeve C, Halley DJ, Niermeijer MF, Klijn JG, Meijers-Heijboer H (2001). "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. doi:10.1016/S0959-8049(01)00244-1. PMID 11597388.
  24. ^ Huusko P, Pääkkönen K, Launonen V, Poyhonen M, Blanco G, Kauppila A, Puistola U, Kiviniemi H, Kujala M, Leisti J, Winqvist R (1998). "Evidence of founder mutations in Finnish BRCA1 and BRCA2 families". American Journal of Human Genetics 62 (6): 1544–1548. doi:10.1086/301880. PMC 1377159. PMID 9585608. //
  25. ^ Pääkkönen K, Sauramo S, Sarantaus L, Vahteristo P, Hartikainen A, Vehmanen P, Ignatius J, Ollikainen V, Kaariainen H, Vauramo E, Nevanlinna H, Krahe R, Holli K, Kere J (2001). "Involvement of BRCA1 and BRCA2 in breast cancer in a western Finnish sub-population". Genetic Epidemiology 20 (2): 239–246. doi:10.1002/1098-2272(200102)20:2<239::AID-GEPI6>3.0.CO;2-Y. PMID 11180449.
  26. ^ Tonin PN, Mes-Masson AM, Narod SA, Ghadirian P, Provencher D (1999). "Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history". Clinical Genetics 55 (5): 318–324. doi:10.1034/j.1399-0004.1999.550504.x. PMID 10422801.
  27. ^ Van Der Looij M, Szabo C, Besznyak I, Liszka G, Csokay B, Pulay T, Toth J, Devilee P, King MC, Olah E (2000). "Prevalence of founder BRCA1 and BRCA2 mutations among breast and ovarian cancer patients in Hungary". International Journal of Cancer 86 (5): 737–740. doi:10.1002/(SICI)1097-0215(20000601)86:5<737::AID-IJC21>3.0.CO;2-1. PMID 10797299.
  28. ^ Pisano M, Cossu A, Persico I, Palmieri G, Angius A, Casu G, Palomba G, Sarobba MG, Rocca PC, Dedola MF, Olmeo N, Pasca A, Budroni M, Marras V, Pisano A, Farris A, Massarelli G, Pirastu M, Tanda F (2000). "Identification of a founder BRCA2 mutation in Sardinia". British Journal of Cancer 82 (3): 553–559. doi:10.1054/bjoc.1999.0963. PMC 2363305. PMID 10682665. //
  29. ^ a b 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. PMC 2747571. PMID 12698193. //
  30. ^ Liede A, Malik IA, Aziz Z, Rios PD, Kwan E, Narod, SA (2002). "Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan". American Journal of Human Genetics 71 (3): 595–606. doi:10.1086/342506. PMC 379195. PMID 12181777. //
  31. ^ Krajc M, De Greve J, Goelen G, Teugels E (2002). "BRCA2 founder mutation in Slovenian breast cancer families". European Journal of Human Genetics 10 (12): 879–882. doi:10.1038/sj.ejhg.5200886. PMID 12461697.
  32. ^ Osorio A, Robledo M, Martinez B, Cebrian A, San Roman JM, Albertos J, Lobo F, Benitez J (1998). "Molecular analysis of the BRCA2 gene in 16 breast/ovarian cancer Spanish families". Clinical Genetics 54 (7): 142–147. doi:10.1054/bjoc.1999.1089. PMC 2374482. PMID 10755399. //
  33. ^ Neuhausen SL (2000). "Founder populations and their uses for breast cancer genetics". Cancer Research 2 (2): 77–81. doi:10.1186/bcr36. PMC 139426. PMID 11250694. //
  34. ^ a b c d e f Dong Y, Hakimi Mohamed-Ali, Chen Xiaowei, Kumaraswamy Easwari, Cooch Neil S, Godwin Andrew K, Shiekhattar Ramin (November 2003). "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. doi:10.1016/S1097-2765(03)00424-6. PMID 14636569.
  35. ^ Ryser S, Dizin Eva, Jefford Charles Edward, Delaval Bénédicte, Gagos Sarantis, Christodoulidou Agni, Krause Karl-Heinz, Birnbaum Daniel, Irminger-Finger Irmgard (February 2009). "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. doi:10.1158/0008-5472.CAN-08-2134. PMID 19176389.
  36. ^ a b Liu J, Yuan Y, Huan J, Shen Z (January 2001). "Inhibition of breast and brain cancer cell growth by BCCIPalpha, an evolutionarily conserved nuclear protein that interacts with BRCA2". Oncogene 20 (3): 336–45. doi:10.1038/sj.onc.1204098. PMID 11313963.
  37. ^ a b Sarkisian CJ, Master S R, Huber L J, Ha S I, Chodosh L A (October 2001). "Analysis of murine Brca2 reveals conservation of protein-protein interactions but differences in nuclear localization signals". J. Biol. Chem. 276 (40): 37640–8. doi:10.1074/jbc.M106281200. PMID 11477095.
  38. ^ a b Chen J, Silver D P, Walpita D, Cantor S B, Gazdar A F, Tomlinson G, Couch F J, Weber B L, Ashley T, Livingston D M, Scully R (September 1998). "Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells". Mol. Cell 2 (3): 317–28. doi:10.1016/S1097-2765(00)80276-2. PMID 9774970.
  39. ^ Reuter TY, Medhurst Annette L, Waisfisz Quinten, Zhi Yu, Herterich Sabine, Hoehn Holger, Gross Hans J, Joenje Hans, Hoatlin Maureen E, Mathew Christopher G, Huber Pia A J (October 2003). "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. doi:10.1016/S0014-4827(03)00261-1. PMID 14499622.
  40. ^ Futamura M, Arakawa H, Matsuda K, Katagiri T, Saji S, Miki Y, Nakamura Y (March 2000). "Potential role of BRCA2 in a mitotic checkpoint after phosphorylation by hBUBR1". Cancer Res. 60 (6): 1531–5. PMID 10749118.
  41. ^ Siddique H, Rao VN, Reddy ES (August 2009). "CBP-mediated post-translational N-glycosylation of BRCA2". Int J Oncol. 35 (2): 16387–91. PMID 19578754.
  42. ^ Hughes-Davies L, Huntsman David, Ruas Margarida, Fuks Francois, Bye Jacqueline, Chin Suet-Feung, Milner Jonathon, Brown Lindsay A, Hsu Forrest, Gilks Blake, Nielsen Torsten, Schulzer Michael, Chia Stephen, Ragaz Joseph, Cahn Anthony, Linger Lori, Ozdag Hilal, Cattaneo Elena, Jordanova E S, Schuuring Edward, Yu David S, Venkitaraman Ashok, Ponder Bruce, Doherty Aidan, Aparicio Samuel, Bentley David, Theillet Charles, Ponting Chris P, Caldas Carlos, Kouzarides Tony (November 2003). "EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer". Cell 115 (5): 523–35. doi:10.1016/S0092-8674(03)00930-9. PMID 14651845.
  43. ^ Wang XZ, Andreassen Paul R, D'Andrea Alan D (July 2004). "Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin". Mol. Cell. Biol. 24 (13): 5850–62. doi:10.1128/MCB.24.13.5850-5862.2004. PMC 480901. PMID 15199141. //
  44. ^ Hussain S, Wilson James B, Medhurst Annette L, Hejna James, Witt Emily, Ananth Sahana, Davies Adelina, Masson Jean-Yves, Moses Robb, West Stephen C, de Winter Johan P, Ashworth Alan, Jones Nigel J, Mathew Christopher G (June 2004). "Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways". Hum. Mol. Genet. 13 (12): 1241–8. doi:10.1093/hmg/ddh135. PMID 15115758.
  45. ^ Hejna J, Holtorf Megan, Hines Jennie, Mathewson Lauren, Hemphill Aaron, Al-Dhalimy Muhsen, Olson Susan B, Moses Robb E (April 2008). "Tip60 is required for DNA interstrand cross-link repair in the Fanconi anemia pathway". J. Biol. Chem. 283 (15): 9844–51. doi:10.1074/jbc.M709076200. PMC 2398728. PMID 18263878. //
  46. ^ Hussain S, Witt Emily, Huber Pia A J, Medhurst Annette L, Ashworth Alan, Mathew Christopher G (October 2003). "Direct interaction of the Fanconi anaemia protein FANCG with BRCA2/FANCD1". Hum. Mol. Genet. 12 (19): 2503–10. doi:10.1093/hmg/ddg266. PMID 12915460.
  47. ^ Yuan Y, Shen Z (December 2001). "Interaction with BRCA2 suggests a role for filamin-1 (hsFLNa) in DNA damage response". J. Biol. Chem. 276 (51): 48318–24. doi:10.1074/jbc.M102557200. PMID 11602572.
  48. ^ Marmorstein LY, Kinev A V, Chan G K, Bochar D A, Beniya H, Epstein J A, Yen T J, Shiekhattar R (January 2001). "A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression". Cell 104 (2): 247–57. doi:10.1016/S0092-8674(01)00209-4. PMID 11207365.
  49. ^ Hakimi M-A, Bochar Daniel A, Chenoweth Josh, Lane William S, Mandel Gail, Shiekhattar Ramin (May. 2002). "A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes". Proc. Natl. Acad. Sci. U.S.A. 99 (11): 7420–5. doi:10.1073/pnas.112008599. PMC 124246. PMID 12032298. //
  50. ^ a b c Marmorstein LY, Ouchi T, Aaronson S A (November 1998). "The BRCA2 gene product functionally interacts with p53 and RAD51". Proc. Natl. Acad. Sci. U.S.A. 95 (23): 13869–74. doi:10.1073/pnas.95.23.13869. PMC 24938. PMID 9811893. //
  51. ^ "Entrez Gene: PALB2 partner and localizer of BRCA2".
  52. ^ a b c Lin H-R, Ting Nicholas S Y, Qin Jun, Lee Wen-Hwa (September 2003). "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. doi:10.1074/jbc.M210659200. PMID 12815053.
  53. ^ Fuks F, Milner J, Kouzarides T (November 1998). "BRCA2 associates with acetyltransferase activity when bound to P/CAF". Oncogene 17 (19): 2531–4. doi:10.1038/sj.onc.1202475. PMID 9824164.
  54. ^ Lee MY, Daniels Matthew J, Venkitaraman Ashok R (January 2004). "Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression". Oncogene 23 (4): 865–72. doi:10.1038/sj.onc.1207223. PMID 14647413.
  55. ^ Sharan SK, Morimatsu M, Albrecht U, Lim D S, Regel E, Dinh C, Sands A, Eichele G, Hasty P, Bradley A (April 1997). "Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2". Nature 386 (6627): 804–10. doi:10.1038/386804a0. PMID 9126738.
  56. ^ Yu DS, Sonoda Eiichiro, Takeda Shunichi, Huang Christopher L H, Pellegrini Luca, Blundell Tom L, Venkitaraman Ashok R (October 2003). "Dynamic control of Rad51 recombinase by self-association and interaction with BRCA2". Mol. Cell 12 (4): 1029–41. doi:10.1016/S1097-2765(03)00394-0. PMID 14580352.
  57. ^ a b Chen PL, Chen C F, Chen Y, Xiao J, Sharp Z D, Lee W H (April 1998). "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. doi:10.1073/pnas.95.9.5287. PMC 20253. PMID 9560268. //
  58. ^ a b Wong AK, Pero R, Ormonde P A, Tavtigian S V, Bartel P L (December 1997). "RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2". J. Biol. Chem. 272 (51): 31941–4. doi:10.1074/jbc.272.51.31941. PMID 9405383.
  59. ^ Katagiri T, Saito H, Shinohara A, Ogawa H, Kamada N, Nakamura Y, Miki Y (March 1998). "Multiple possible sites of BRCA2 interacting with DNA repair protein RAD51". Genes Chromosomes Cancer 21 (3): 217–22. doi:10.1002/(SICI)1098-2264(199803)21:3<217::AID-GCC5>3.0.CO;2-2. PMID 9523196.
  60. ^ Pellegrini L, Yu David S, Lo Thomas, Anand Shubha, Lee MiYoung, Blundell Tom L, Venkitaraman Ashok R (November 2002). "Insights into DNA recombination from the structure of a RAD51-BRCA2 complex". Nature 420 (6913): 287–93. doi:10.1038/nature01230. PMID 12442171.
  61. ^ Tarsounas M, Davies Adelina A, West Stephen C (January 2004). "RAD51 localization and activation following DNA damage". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 359 (1441): 87–93. doi:10.1098/rstb.2003.1368. PMC 1693300. PMID 15065660. //
  62. ^ Wong JMS, Ionescu Daniela, Ingles C James (January 2003). "Interaction between BRCA2 and replication protein A is compromised by a cancer-predisposing mutation in BRCA2". Oncogene 22 (1): 28–33. doi:10.1038/sj.onc.1206071. PMID 12527904.
  63. ^ Marston NJ, Richards W J, Hughes D, Bertwistle D, Marshall C J, Ashworth A (July 1999). "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. PMC 84261. PMID 10373512. //
  64. ^ a b c d e Yang H, Jeffrey Philip D, Miller Julie, Kinnucan Elspeth, Sun Yutong, Thoma Nicolas H, Zheng Ning, Chen Phang-Lang, Lee Wen-Hwa, Pavletich Nikola P (September 2002). "BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure". Science 297 (5588): 1837–48. doi:10.1126/science.297.5588.1837. PMID 12228710.
  65. ^ Preobrazhenska O, Yakymovych Mariya, Kanamoto Takashi, Yakymovych Ihor, Stoika Rostyslav, Heldin Carl-Henrik, Souchelnytskyi Serhiy (August 2002). "BRCA2 and Smad3 synergize in regulation of gene transcription". Oncogene 21 (36): 5660–4. doi:10.1038/sj.onc.1205732. PMID 12165866.
  66. ^ Bork P, Blomberg N, Nilges M (May 1996). "Internal repeats in the BRCA2 protein sequence". Nat. Genet. 13 (1): 22–3. doi:10.1038/ng0596-22. PMID 8673099.
  67. ^ Robert Cook-Deegan, MD et al (2010) Impact of Gene Patents and Licensing Practices on Access to Genetic Testing for Inherited Susceptibility to Cancer: Comparing Breast and Ovarian Cancers to Colon Cancers: Patents and Licensing for Breast, Ovarian and Colon Cancer Testing Genet Med.12(4 Suppl): S15–S38.
  68. ^ Benowitz S (January 2003). "European groups oppose Myriad's latest patent on BRCA1". J. Natl. Cancer Inst. 95 (1): 8–9. doi:10.1093/jnci/95.1.8. PMID 12509391.
  69. ^ Conley J, Vorhous D, Cook-Deegan J (2011-03-01). "How Will Myriad Respond to the Next Generation of BRCA Testing?". Robinson, Bradshaw, and Hinson. Retrieved 2012-12-09.
  70. ^ "Genetics and Patenting". Human Genome Project Information. U.S. Department of Energy Genome Programs. 2010-07-07.

Further reading

  • Zou JP, Hirose Y, Siddique H, Rao VN, Reddy ES (1999). "Structure and expression of variant BRCA2a lacking the transactivation domain". Oncology reports 6 (2): 437–40. PMID 10023017.
  • Venkitaraman AR (2001). "Chromosome stability, DNA recombination and the BRCA2 tumour suppressor". Curr. Opin. Cell Biol. 13 (3): 338–43. doi:10.1016/S0955-0674(00)00217-9. PMID 11343905.
  • Orelli BJ, Bishop DK (2001). "BRCA2 and homologous recombination". Breast Cancer Res. 3 (5): 294–8. doi:10.1186/bcr310. PMC 138691. PMID 11597317. //
  • Daniel DC (2002). "Highlight: BRCA1 and BRCA2 proteins in breast cancer". Microsc. Res. Tech. 59 (1): 68–83. doi:10.1002/jemt.10178. PMID 12242698.
  • Tutt A, Ashworth A (2003). "The relationship between the roles of BRCA genes in DNA repair and cancer predisposition". Trends in molecular medicine 8 (12): 571–6. doi:10.1016/S1471-4914(02)02434-6. PMID 12470990.
  • Gonçalves A, Viens P, Sobol H, et al. (2005). "[Molecular alterations in breast cancer: clinical implications and new analytical tools]". La Revue de médecine interne / fondée ... Par la Société nationale francaise de médecine interne 26 (6): 470–8. doi:10.1016/j.revmed.2004.11.012. PMID 15936476.
  • Hay T, Clarke AR (2005). "DNA damage hypersensitivity in cells lacking BRCA2: a review of in vitro and in vivo data". Biochem. Soc. Trans. 33 (Pt 4): 715–7. doi:10.1042/BST0330715. PMID 16042582.
  • Domchek SM, Weber BL (2006). "Clinical management of BRCA1 and BRCA2 mutation carriers". Oncogene 25 (43): 5825–31. doi:10.1038/sj.onc.1209881. PMID 16998496.
  • Honrado E, Osorio A, Palacios J, Benitez J (2006). "Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations". Oncogene 25 (43): 5837–45. doi:10.1038/sj.onc.1209875. PMID 16998498.

External links

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