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Versione delle 12:03, 14 ago 2009

BRCA2 (dall'inglese Breast Cancer Type 2 susceptibility protein, proteina per la sensibilità al cancro della mammella tipo 2) è una proteina che negli esseri umani è codificata dal gene BRCA2.[1] BRCA2 appartiene alla famiglia dei geni oncosoppressori[2][3] e la proteina codificata da questo gene è coinvolta nella riparazione dei tratti cromosomici danneggiati con un ruolo importante nella riparazione priva di errori delle rotture nel doppio filamento di DNA.[4]

Il gene BRCA2 è situato sul braccio (q) lungo del cromosoma 13, nella posizione 12.3 (13q12.3), dalla coppia di basi 31,787,616 alla coppia 31,871,804.[1]

Struttura e funzione

Sebbene le strutture di BRCA1 e BRCA2 siano molto differenti, tuttavia alcune funzioni dei due geni sono correlate: le proteine codificate da entrambi i geni sono essenziali per la riparazione del DNA danneggiato. La proteina BRCA2 si lega e regola la proteina codificata dal gene RAD51 per correggere le rotture nel DNA. Queste rotture possono essere causate da radiazioni naturali o mediche o dall'esposizione ad altri agenti ambientali, ma possono anche avvenire quando i cromosomi si scambiano materiale genetico durante la meiosi (crossing over). Anche la proteina BRCA1 interagisce con la proteina RAD51. Riparando il DNA, queste tre proteine hanno un ruolo fondamentale nel mantenere intatta la stabilità del genoma umano e nel prevenire riassetti genetici pericolosi, che possano condurre a neoplasie ematologiche.[4]

Come BRCA1, probabilmente anche BRCA2 regola l'attività di altri geni ed ha un ruolo importante nello sviluppo embrionale.

Importanza clinica

Certain variations of the BRCA2 gene cause an increased risk for breast cancer. 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.[4]

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.

Storia

The BRCA2 gene was discovered in 1995 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 the National Cycle Network route 11, and can be seen from the Cambridge-London Liverpool Street train.

Interazioni

BRCA2 has been shown to interact with BRE,[5] Filamin,[6] Replication protein A1,[7] BRCC3,[5] RAD51,[5][8][9][10][11][12][13][14][15][16][17][18][19] BARD1,[5][20] HMG20B,[21][22] FANCD2,[23][24][25] FANCG,[26] BRCA1,[5][12][18][27] PLK1,[9][28] PCAF,[9][29] C11orf30,[30] P53,[5][19] BUB1B,[31] BCCIP,[17] SHFM1[32][33] and Mothers against decapentaplegic homolog 3.[34]

Note

  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., Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13, in Science (New York, N.Y.), vol. 265, n. 5181, September 1994, pp. 2088–90, DOI:10.1126/science.8091231.
  2. ^ Duncan JA, Reeves JR, Cooke TG, BRCA1 and BRCA2 proteins: roles in health and disease, in Molecular pathology : MP, vol. 51, n. 5, October 1998, pp. 237–47, DOI:10.1136/mp.51.5.237.
  3. ^ Yoshida K, Miki Y, Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage (PDF), in Cancer science, vol. 95, n. 11, November 2004, pp. 866–71, DOI:10.1111/j.1349-7006.2004.tb02195.x.
  4. ^ a b c 4. Friedenson B. (2008) [1] Breast cancer genes protect against some leukemias and lymphomas
  5. ^ a b c d e f Yuanshu Dong, Hakimi Mohamed-Ali, Chen Xiaowei, Kumaraswamy Easwari, Cooch Neil S, Godwin Andrew K, Shiekhattar Ramin, Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair, in Mol. Cell, vol. 12, n. 5, Nov. 2003, pp. 1087-99.
  6. ^ Y Yuan, Shen Z, Interaction with BRCA2 suggests a role for filamin-1 (hsFLNa) in DNA damage response, in J. Biol. Chem., vol. 276, n. 51, Dec. 2001, pp. 48318-24, DOI:10.1074/jbc.M102557200.
  7. ^ Johnson M S Wong, Ionescu Daniela, Ingles C James, Interaction between BRCA2 and replication protein A is compromised by a cancer-predisposing mutation in BRCA2, in Oncogene, vol. 22, n. 1, Jan. 2003, pp. 28-33, DOI:10.1038/sj.onc.1206071.
  8. ^ S K Sharan, Morimatsu M, Albrecht U, Lim D S, Regel E, Dinh C, Sands A, Eichele G, Hasty P, Bradley A, Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2, in Nature, vol. 386, n. 6627, Apr. 1997, pp. 804-10, DOI:10.1038/386804a0.
  9. ^ a b c Horng-Ru Lin, Ting Nicholas S Y, Qin Jun, Lee Wen-Hwa, M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex, in J. Biol. Chem., vol. 278, n. 38, Sep. 2003, pp. 35979-87, DOI:10.1074/jbc.M210659200.
  10. ^ David S Yu, Sonoda Eiichiro, Takeda Shunichi, Huang Christopher L H, Pellegrini Luca, Blundell Tom L, Venkitaraman Ashok R, Dynamic control of Rad51 recombinase by self-association and interaction with BRCA2, in Mol. Cell, vol. 12, n. 4, Oct. 2003, pp. 1029-41.
  11. ^ P L Chen, Chen C F, Chen Y, Xiao J, Sharp Z D, Lee W H, The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment, in Proc. Natl. Acad. Sci. U.S.A., vol. 95, n. 9, Apr. 1998, pp. 5287-92.
  12. ^ a b C J Sarkisian, Master S R, Huber L J, Ha S I, Chodosh L A, Analysis of murine Brca2 reveals conservation of protein-protein interactions but differences in nuclear localization signals, in J. Biol. Chem., vol. 276, n. 40, Oct. 2001, pp. 37640-8, DOI:10.1074/jbc.M106281200.
  13. ^ A K Wong, Pero R, Ormonde P A, Tavtigian S V, Bartel P L, RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2, in J. Biol. Chem., vol. 272, n. 51, Dec. 1997, pp. 31941-4.
  14. ^ T Katagiri, Saito H, Shinohara A, Ogawa H, Kamada N, Nakamura Y, Miki Y, Multiple possible sites of BRCA2 interacting with DNA repair protein RAD51, in Genes Chromosomes Cancer, vol. 21, n. 3, Mar. 1998, pp. 217-22.
  15. ^ Luca Pellegrini, Yu David S, Lo Thomas, Anand Shubha, Lee MiYoung, Blundell Tom L, Venkitaraman Ashok R, Insights into DNA recombination from the structure of a RAD51-BRCA2 complex, in Nature, vol. 420, n. 6913, Nov. 2002, pp. 287-93, DOI:10.1038/nature01230.
  16. ^ Madalena Tarsounas, Davies Adelina A, West Stephen C, RAD51 localization and activation following DNA damage, in Philos. Trans. R. Soc. Lond., B, Biol. Sci., vol. 359, n. 1441, Jan. 2004, pp. 87-93, DOI:10.1098/rstb.2003.1368.
  17. ^ a b J Liu, Yuan Y, Huan J, Shen Z, Inhibition of breast and brain cancer cell growth by BCCIPalpha, an evolutionarily conserved nuclear protein that interacts with BRCA2, in Oncogene, vol. 20, n. 3, Jan. 2001, pp. 336-45, DOI:10.1038/sj.onc.1204098.
  18. ^ a b J Chen, 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, Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells, in Mol. Cell, vol. 2, n. 3, Sep. 1998, pp. 317-28.
  19. ^ a b L Y Marmorstein, Ouchi T, Aaronson S A, The BRCA2 gene product functionally interacts with p53 and RAD51, in Proc. Natl. Acad. Sci. U.S.A., vol. 95, n. 23, Nov. 1998, pp. 13869-74.
  20. ^ Stephan Ryser, Dizin Eva, Jefford Charles Edward, Delaval Bénédicte, Gagos Sarantis, Christodoulidou Agni, Krause Karl-Heinz, Birnbaum Daniel, Irminger-Finger Irmgard, Distinct roles of BARD1 isoforms in mitosis: full-length BARD1 mediates Aurora B degradation, cancer-associated BARD1beta scaffolds Aurora B and BRCA2, in Cancer Res., vol. 69, n. 3, Feb. 2009, pp. 1125-34, DOI:10.1158/0008-5472.CAN-08-2134.
  21. ^ L Y Marmorstein, Kinev A V, Chan G K, Bochar D A, Beniya H, Epstein J A, Yen T J, Shiekhattar R, A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression, in Cell, vol. 104, n. 2, Jan. 2001, pp. 247-57.
  22. ^ Mohamed-Ali Hakimi, Bochar Daniel A, Chenoweth Josh, Lane William S, Mandel Gail, Shiekhattar Ramin, A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes, in Proc. Natl. Acad. Sci. U.S.A., vol. 99, n. 11, May. 2002, pp. 7420-5, DOI:10.1073/pnas.112008599.
  23. ^ XiaoZhe Wang, Andreassen Paul R, D'Andrea Alan D, Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin, in Mol. Cell. Biol., vol. 24, n. 13, Jul. 2004, pp. 5850-62, DOI:10.1128/MCB.24.13.5850-5862.2004.
  24. ^ Shobbir Hussain, 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, Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways, in Hum. Mol. Genet., vol. 13, n. 12, Jun. 2004, pp. 1241-8, DOI:10.1093/hmg/ddh135.
  25. ^ James Hejna, Holtorf Megan, Hines Jennie, Mathewson Lauren, Hemphill Aaron, Al-Dhalimy Muhsen, Olson Susan B, Moses Robb E, Tip60 is required for DNA interstrand cross-link repair in the Fanconi anemia pathway, in J. Biol. Chem., vol. 283, n. 15, Apr. 2008, pp. 9844-51, DOI:10.1074/jbc.M709076200.
  26. ^ Shobbir Hussain, Witt Emily, Huber Pia A J, Medhurst Annette L, Ashworth Alan, Mathew Christopher G, Direct interaction of the Fanconi anaemia protein FANCG with BRCA2/FANCD1, in Hum. Mol. Genet., vol. 12, n. 19, Oct. 2003, pp. 2503-10, DOI:10.1093/hmg/ddg266.
  27. ^ Tanja Y Reuter, 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, Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport, in Exp. Cell Res., vol. 289, n. 2, Oct. 2003, pp. 211-21.
  28. ^ MiYoung Lee, Daniels Matthew J, Venkitaraman Ashok R, Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression, in Oncogene, vol. 23, n. 4, Jan. 2004, pp. 865-72, DOI:10.1038/sj.onc.1207223.
  29. ^ F Fuks, Milner J, Kouzarides T, BRCA2 associates with acetyltransferase activity when bound to P/CAF, in Oncogene, vol. 17, n. 19, Nov. 1998, pp. 2531-4, DOI:10.1038/sj.onc.1202475.
  30. ^ Luke Hughes-Davies, 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, EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer, in Cell, vol. 115, n. 5, Nov. 2003, pp. 523-35.
  31. ^ M Futamura, Arakawa H, Matsuda K, Katagiri T, Saji S, Miki Y, Nakamura Y, Potential role of BRCA2 in a mitotic checkpoint after phosphorylation by hBUBR1, in Cancer Res., vol. 60, n. 6, Mar. 2000, pp. 1531-5.
  32. ^ N J Marston, Richards W J, Hughes D, Bertwistle D, Marshall C J, Ashworth A, Interaction between the product of the breast cancer susceptibility gene BRCA2 and DSS1, a protein functionally conserved from yeast to mammals, in Mol. Cell. Biol., vol. 19, n. 7, Jul. 1999, pp. 4633-42.
  33. ^ Haijuan Yang, Jeffrey Philip D, Miller Julie, Kinnucan Elspeth, Sun Yutong, Thoma Nicolas H, Zheng Ning, Chen Phang-Lang, Lee Wen-Hwa, Pavletich Nikola P, BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure, in Science, vol. 297, n. 5588, Sep. 2002, pp. 1837-48, DOI:10.1126/science.297.5588.1837.
  34. ^ Olena Preobrazhenska, Yakymovych Mariya, Kanamoto Takashi, Yakymovych Ihor, Stoika Rostyslav, Heldin Carl-Henrik, Souchelnytskyi Serhiy, BRCA2 and Smad3 synergize in regulation of gene transcription, in Oncogene, vol. 21, n. 36, Aug. 2002, pp. 5660-4, DOI:10.1038/sj.onc.1205732.

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