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Gene Review

BRCA1  -  breast cancer 1, early onset

Homo sapiens

 
 
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Disease relevance of BRCA1

 

Psychiatry related information on BRCA1

  • The purpose of this report is to review the current state of knowledge of BRCA1 and BRCA2, the biology of associated tumors, and possible risk reduction strategies in women with these deleterious mutations [9].
  • In contrast to the results with the micronucleus assay, we found no significant individual difference between women with and without a BRCA1 mutation with respect to the induction and repair of DNA damage in the alkaline comet assay [10].
  • BRCA1 and BRCA2 gene mutations: decision-making dilemmas concerning testing and management [11].
  • At follow-up, noncarriers of BRCA1 mutations showed statistically significant reductions in depressive symptoms and functional impairment compared with carriers and nontested individuals [12].
  • The goals of the present study were to describe rates of completing a psychosocial telephone counseling (PTC) intervention that was offered to female BRCA1/2 mutation carriers and to identify sociodemographic and psychological factors associated with decisions to complete the intervention [13].
 

High impact information on BRCA1

  • The significant risk factor for development of ovarian cancer is advancing age, although there is clearly a genetic predisposition--often associated with the BRCA1 and BRCA2 genes--in at least 5% to 10% of all epithelial ovarian cancers [14].
  • The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia [15].
  • Here we show that the protein defective in individuals with Fanconi anemia belonging to complementation group B is an essential component of the nuclear protein 'core complex' responsible for monoubiquitination of FANCD2, a key event in the DNA-damage response pathway associated with Fanconi anemia and BRCA [16].
  • Here we show that BRCA1 is essential for activating the Chk1 kinase that regulates DNA damage-induced G2/M arrest [17].
  • Thus, BRCA1 controls the expression, phosphorylation and cellular localization of Cdc25C and Cdc2/cyclin B kinase-proteins that are crucial for the G2/M transition [17].
 

Chemical compound and disease context of BRCA1

 

Biological context of BRCA1

 

Anatomical context of BRCA1

 

Associations of BRCA1 with chemical compounds

  • Phosphorylation of BRCA1 at serine 988 is required for the release of BRCA1 from hCds1 [22].
  • Ectopic expression of wild-type, but not mutated, BRCA1 in these cells rendered them less sensitive to the DNA damage agent, methyl methanesulfonate [27].
  • In this study, we show that BRCA1 phosphorylation is only partially ATM dependent in response to IR and ATM independent in response to treatment with UV light, or the DNA replication inhibitors hydroxyurea (HU) and aphidicolin (APH) [28].
  • In this study, we show that BLM function is specifically required to properly relocalize the RAD50/MRE11/NBS1 (RMN) complex at sites of replication arrest, but is not essential in the activation of BRCA1 either after stalled replication forks or gamma-rays [29].
  • By using UBR60 cells, which carry tetracycline-regulated expression of BRCA1, we demonstrated that BRCA1 binds to transcription factor OCT-1 and up-regulates the transcription of MAD2 [30].
  • The proteasome-mediated degradation of BRCA1 and BARD1 also occurs during the cAMP-dependent steroidogenic process [31].
  • The enhanced ER-alpha activity attributable to BRCA1 knockdown was dependent, in part, on serine residues 167 and 118 of ER-alpha [32].
 

Physical interactions of BRCA1

  • The FANCD2 protein, therefore, provides the missing link between the FA protein complex and the cellular BRCA1 repair machinery [33].
  • Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex [34].
  • Significantly, STAT1 proteins mutated at Ser-727 bind poorly to BRCA1, reinforcing the importance of Ser-727 in the recruitment of transcriptional coactivators by STAT proteins [35].
  • The second BRCT domain of BRCA1 proteins interacts with p53 and stimulates transcription from the p21WAF1/CIP1 promoter [36].
  • Immunoprecipitation assay showed that BRCA1 interacted with JAK1 and JAK2 [21].
 

Enzymatic interactions of BRCA1

  • BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site [37].
  • Brca1 is hyperphosphorylated in response to DNA damage and co-localizes with Rad51, a protein involved in homologous-recombination, and Nbs1.Mre11.Rad50, a complex required for both homologous-recombination and nonhomologous end joining repair of damaged DNA [38].
  • ATR phosphorylates BRCA1 on six Ser/Thr residues, including Ser 1423, in vitro [28].
  • We then delineated the biochemical characteristics of the complex and found that BRCA1 interacts solely with the phosphorylated and inactive form of ACCA (P-ACCA) [39].
  • Here we report the crystal structure of the BRCT repeats of human BRCA1 bound to a phosphorylated BACH1 peptide at 2.3 A resolution [40].
 

Co-localisations of BRCA1

 

Regulatory relationships of BRCA1

 

Other interactions of BRCA1

  • Our results indicate that somatic BRCA2 mutations, like somatic mutations in the BRCA1 gene, are very rare in primary breast cancers [48].
  • Given the suspected role of BRCA1/BARD1 in DNA repair, we tested whether inhibition of mRNA processing is linked to DNA damage [49].
  • A key step in this pathway is monoubiquitination of FANCD2, resulting in the redistribution of FANCD2 to nuclear foci containing BRCA1 (ref. 3). The underlying mechanism is unclear because the five Fanconi anemia proteins known to be required for this ubiquitination have no recognizable ubiquitin ligase motifs [50].
  • RNA interference (RNAi) of MCPH1 have implicated the protein it encodes as a DNA-damage response protein that regulates the transcription of Chk1 and BRCA1, two genes involved in the response to DNA damage [51].
  • A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein [52].
  • Taken together, our results indicate that up-regulation of HR provides a permissive genetic context for cells lacking BRCA1 function by circumventing its requirement in RAD51 subnuclear assembly [53].
  • Collectively, these results indicate that cyclin D1/cdk4-mediated phosphorylation of BRCA1 inhibits the ability of BRCA1 to be recruited to particular promoters in vivo [54].
  • These findings illustrate a molecular mechanism for estrogen/ERalpha signals in BRCA1-associated tissue-specific tumor formation, and identify several key elements in the estrogen/ERalpha-signaling cascade that can serve as potential therapeutic targets for BRCA1-associated tumorigenesis [55].
 

Analytical, diagnostic and therapeutic context of BRCA1

References

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  2. BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Bochar, D.A., Wang, L., Beniya, H., Kinev, A., Xue, Y., Lane, W.S., Wang, W., Kashanchi, F., Shiekhattar, R. Cell (2000) [Pubmed]
  3. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Meijers-Heijboer, H., van den Ouweland, A., Klijn, J., Wasielewski, M., de Snoo, A., Oldenburg, R., Hollestelle, A., Houben, M., Crepin, E., van Veghel-Plandsoen, M., Elstrodt, F., van Duijn, C., Bartels, C., Meijers, C., Schutte, M., McGuffog, L., Thompson, D., Easton, D., Sodha, N., Seal, S., Barfoot, R., Mangion, J., Chang-Claude, J., Eccles, D., Eeles, R., Evans, D.G., Houlston, R., Murday, V., Narod, S., Peretz, T., Peto, J., Phelan, C., Zhang, H.X., Szabo, C., Devilee, P., Goldgar, D., Futreal, P.A., Nathanson, K.L., Weber, B., Rahman, N., Stratton, M.R. Nat. Genet. (2002) [Pubmed]
  4. The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair. Bridge, W.L., Vandenberg, C.J., Franklin, R.J., Hiom, K. Nat. Genet. (2005) [Pubmed]
  5. Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Li, S., Ting, N.S., Zheng, L., Chen, P.L., Ziv, Y., Shiloh, Y., Lee, E.Y., Lee, W.H. Nature (2000) [Pubmed]
  6. BRCA1 mRNA expression levels predict for overall survival in ovarian cancer after chemotherapy. Quinn, J.E., James, C.R., Stewart, G.E., Mulligan, J.M., White, P., Chang, G.K., Mullan, P.B., Johnston, P.G., Wilson, R.H., Harkin, D.P. Clin. Cancer Res. (2007) [Pubmed]
  7. Tumor suppressor BRCA1 is expressed in prostate cancer and controls insulin-like growth factor I receptor (IGF-IR) gene transcription in an androgen receptor-dependent manner. Schayek, H., Haugk, K., Sun, S., True, L.D., Plymate, S.R., Werner, H. Clin. Cancer Res. (2009) [Pubmed]
  8. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Sanz, D.J., Acedo, A., Infante, M., Durán, M., Pérez-Cabornero, L., Esteban-Cardeñosa, E., Lastra, E., Pagani, F., Miner, C., Velasco, E.A. Clin. Cancer Res. (2010) [Pubmed]
  9. Clinical management of women with genomic BRCA1 and BRCA2 mutations. Chang, J., Elledge, R.M. Breast Cancer Res. Treat. (2001) [Pubmed]
  10. Mutagen sensitivity of peripheral blood from women carrying a BRCA1 or BRCA2 mutation. Trenz, K., Rothfuss, A., Schütz, P., Speit, G. Mutat. Res. (2002) [Pubmed]
  11. BRCA1 and BRCA2 gene mutations: decision-making dilemmas concerning testing and management. Fasouliotis, S.J., Schenker, J.G. Obstetrical & gynecological survey. (2000) [Pubmed]
  12. BRCA1 testing in families with hereditary breast-ovarian cancer. A prospective study of patient decision making and outcomes. Lerman, C., Narod, S., Schulman, K., Hughes, C., Gomez-Caminero, A., Bonney, G., Gold, K., Trock, B., Main, D., Lynch, J., Fulmore, C., Snyder, C., Lemon, S.J., Conway, T., Tonin, P., Lenoir, G., Lynch, H. JAMA (1996) [Pubmed]
  13. Predictors of participation in psychosocial telephone counseling following genetic testing for BRCA1 and BRCA2 mutations. Halbert, C.H., Wenzel, L., Lerman, C., Peshkin, B.N., Narod, S., Marcus, A., Corio, C., Demarco, T., Bellamy, S. Cancer Epidemiol. Biomarkers Prev. (2004) [Pubmed]
  14. Epithelial ovarian cancer: prevention, diagnosis, and treatment. Partridge, E.E., Barnes, M.N. CA: a cancer journal for clinicians. (1999) [Pubmed]
  15. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Levran, O., Attwooll, C., Henry, R.T., Milton, K.L., Neveling, K., Rio, P., Batish, S.D., Kalb, R., Velleuer, E., Barral, S., Ott, J., Petrini, J., Schindler, D., Hanenberg, H., Auerbach, A.D. Nat. Genet. (2005) [Pubmed]
  16. X-linked inheritance of Fanconi anemia complementation group B. Meetei, A.R., Levitus, M., Xue, Y., Medhurst, A.L., Zwaan, M., Ling, C., Rooimans, M.A., Bier, P., Hoatlin, M., Pals, G., de Winter, J.P., Wang, W., Joenje, H. Nat. Genet. (2004) [Pubmed]
  17. BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Yarden, R.I., Pardo-Reoyo, S., Sgagias, M., Cowan, K.H., Brody, L.C. Nat. Genet. (2002) [Pubmed]
  18. BRCA1 inhibits membrane estrogen and growth factor receptor signaling to cell proliferation in breast cancer. Razandi, M., Pedram, A., Rosen, E.M., Levin, E.R. Mol. Cell. Biol. (2004) [Pubmed]
  19. Loss of coordinated androgen regulation in nonmalignant ovarian epithelial cells with BRCA1/2 mutations and ovarian cancer cells. Evangelou, A., Letarte, M., Jurisica, I., Sultan, M., Murphy, K.J., Rosen, B., Brown, T.J. Cancer Res. (2003) [Pubmed]
  20. Polyglutamine repeat length in the AIB1 gene modifies breast cancer susceptibility in BRCA1 carriers. Kadouri, L., Kote-Jarai, Z., Easton, D.F., Hubert, A., Hamoudi, R., Glaser, B., Abeliovich, D., Peretz, T., Eeles, R.A. Int. J. Cancer (2004) [Pubmed]
  21. Constitutive activation of JAK-STAT3 signaling by BRCA1 in human prostate cancer cells. Gao, B., Shen, X., Kunos, G., Meng, Q., Goldberg, I.D., Rosen, E.M., Fan, S. FEBS Lett. (2001) [Pubmed]
  22. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Lee, J.S., Collins, K.M., Brown, A.L., Lee, C.H., Chung, J.H. Nature (2000) [Pubmed]
  23. BRCA1 transcriptionally regulates genes involved in breast tumorigenesis. Welcsh, P.L., Lee, M.K., Gonzalez-Hernandez, R.M., Black, D.J., Mahadevappa, M., Swisher, E.M., Warrington, J.A., King, M.C. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  24. A somatic cell hybrid map of the long arm of human chromosome 17, containing the familial breast cancer locus (BRCA1). Black, D.M., Nicolai, H., Borrow, J., Solomon, E. Am. J. Hum. Genet. (1993) [Pubmed]
  25. Inherited breast and ovarian cancer. Szabo, C.I., King, M.C. Hum. Mol. Genet. (1995) [Pubmed]
  26. BRCA1 inhibition of telomerase activity in cultured cells. Xiong, J., Fan, S., Meng, Q., Schramm, L., Wang, C., Bouzahza, B., Zhou, J., Zafonte, B., Goldberg, I.D., Haddad, B.R., Pestell, R.G., Rosen, E.M. Mol. Cell. Biol. (2003) [Pubmed]
  27. Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Zhong, Q., Chen, C.F., Li, S., Chen, Y., Wang, C.C., Xiao, J., Chen, P.L., Sharp, Z.D., Lee, W.H. Science (1999) [Pubmed]
  28. Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Tibbetts, R.S., Cortez, D., Brumbaugh, K.M., Scully, R., Livingston, D., Elledge, S.J., Abraham, R.T. Genes Dev. (2000) [Pubmed]
  29. Bloom's syndrome protein is required for correct relocalization of RAD50/MRE11/NBS1 complex after replication fork arrest. Franchitto, A., Pichierri, P. J. Cell Biol. (2002) [Pubmed]
  30. A requirement for breast-cancer-associated gene 1 (BRCA1) in the spindle checkpoint. Wang, R.H., Yu, H., Deng, C.X. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  31. Ubiquitination and proteasome-mediated degradation of BRCA1 and BARD1 during steroidogenesis in human ovarian granulosa cells. Lu, Y., Amleh, A., Sun, J., Jin, X., McCullough, S.D., Baer, R., Ren, D., Li, R., Hu, Y. Mol. Endocrinol. (2007) [Pubmed]
  32. Growth factor signaling pathways modulate BRCA1 repression of estrogen receptor-alpha activity. Ma, Y., Hu, C., Riegel, A.T., Fan, S., Rosen, E.M. Mol. Endocrinol. (2007) [Pubmed]
  33. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Garcia-Higuera, I., Taniguchi, T., Ganesan, S., Meyn, M.S., Timmers, C., Hejna, J., Grompe, M., D'Andrea, A.D. Mol. Cell (2001) [Pubmed]
  34. Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex. Brzovic, P.S., Keeffe, J.R., Nishikawa, H., Miyamoto, K., Fox, D., Fukuda, M., Ohta, T., Klevit, R. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  35. Collaboration of signal transducer and activator of transcription 1 (STAT1) and BRCA1 in differential regulation of IFN-gamma target genes. Ouchi, T., Lee, S.W., Ouchi, M., Aaronson, S.A., Horvath, C.M. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  36. The second BRCT domain of BRCA1 proteins interacts with p53 and stimulates transcription from the p21WAF1/CIP1 promoter. Chai, Y.L., Cui, J., Shao, N., Shyam, E., Reddy, P., Rao, V.N. Oncogene (1999) [Pubmed]
  37. BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site. Ruffner, H., Jiang, W., Craig, A.G., Hunter, T., Verma, I.M. Mol. Cell. Biol. (1999) [Pubmed]
  38. Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specific antibodies. Gatei, M., Zhou, B.B., Hobson, K., Scott, S., Young, D., Khanna, K.K. J. Biol. Chem. (2001) [Pubmed]
  39. BRCA1 affects lipid synthesis through its interaction with acetyl-CoA carboxylase. Moreau, K., Dizin, E., Ray, H., Luquain, C., Lefai, E., Foufelle, F., Billaud, M., Lenoir, G.M., Venezia, N.D. J. Biol. Chem. (2006) [Pubmed]
  40. Structure of the BRCT repeats of BRCA1 bound to a BACH1 phosphopeptide: implications for signaling. Shiozaki, E.N., Gu, L., Yan, N., Shi, Y. Mol. Cell (2004) [Pubmed]
  41. Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways. Hussain, S., Wilson, J.B., Medhurst, A.L., Hejna, J., Witt, E., Ananth, S., Davies, A., Masson, J.Y., Moses, R., West, S.C., de Winter, J.P., Ashworth, A., Jones, N.J., Mathew, C.G. Hum. Mol. Genet. (2004) [Pubmed]
  42. BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II). Husain, A., He, G., Venkatraman, E.S., Spriggs, D.R. Cancer Res. (1998) [Pubmed]
  43. p300 Modulates the BRCA1 inhibition of estrogen receptor activity. Fan, S., Ma, Y.X., Wang, C., Yuan, R.Q., Meng, Q., Wang, J.A., Erdos, M., Goldberg, I.D., Webb, P., Kushner, P.J., Pestell, R.G., Rosen, E.M. Cancer Res. (2002) [Pubmed]
  44. Ataxia telangiectasia mutated and checkpoint kinase 2 regulate BRCA1 to promote the fidelity of DNA end-joining. Wang, H.C., Chou, W.C., Shieh, S.Y., Shen, C.Y. Cancer Res. (2006) [Pubmed]
  45. Breast cancer susceptibility gene 1 (BRCAI) is a coactivator of the androgen receptor. Park, J.J., Irvine, R.A., Buchanan, G., Koh, S.S., Park, J.M., Tilley, W.D., Stallcup, M.R., Press, M.F., Coetzee, G.A. Cancer Res. (2000) [Pubmed]
  46. BRCA1-induced apoptosis involves inactivation of ERK1/2 activities. Yan, Y., Haas, J.P., Kim, M., Sgagias, M.K., Cowan, K.H. J. Biol. Chem. (2002) [Pubmed]
  47. Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and phosphorylation in DNA damage checkpoint control. Lou, Z., Chini, C.C., Minter-Dykhouse, K., Chen, J. J. Biol. Chem. (2003) [Pubmed]
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  49. The BARD1-CstF-50 interaction links mRNA 3' end formation to DNA damage and tumor suppression. Kleiman, F.E., Manley, J.L. Cell (2001) [Pubmed]
  50. A novel ubiquitin ligase is deficient in Fanconi anemia. Meetei, A.R., de Winter, J.P., Medhurst, A.L., Wallisch, M., Waisfisz, Q., van de Vrugt, H.J., Oostra, A.B., Yan, Z., Ling, C., Bishop, C.E., Hoatlin, M.E., Joenje, H., Wang, W. Nat. Genet. (2003) [Pubmed]
  51. Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Alderton, G.K., Galbiati, L., Griffith, E., Surinya, K.H., Neitzel, H., Jackson, A.P., Jeggo, P.A., O'Driscoll, M. Nat. Cell Biol. (2006) [Pubmed]
  52. A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. Foray, N., Marot, D., Gabriel, A., Randrianarison, V., Carr, A.M., Perricaudet, M., Ashworth, A., Jeggo, P. EMBO J. (2003) [Pubmed]
  53. RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors. Martin, R.W., Orelli, B.J., Yamazoe, M., Minn, A.J., Takeda, S., Bishop, D.K. Cancer Res. (2007) [Pubmed]
  54. Functional consequences of cyclin D1/BRCA1 interaction in breast cancer cells. Kehn, K., Berro, R., Alhaj, A., Bottazzi, M.E., Yeh, W.I., Klase, Z., Van Duyne, R., Fu, S., Kashanchi, F. Oncogene (2007) [Pubmed]
  55. A role of estrogen/ERalpha signaling in BRCA1-associated tissue-specific tumor formation. Li, W., Xiao, C., Vonderhaar, B.K., Deng, C.X. Oncogene (2007) [Pubmed]
  56. THRA1 and D17S183 flank an interval of < 4 cM for the breast-ovarian cancer gene (BRCA1) on chromosome 17q21. Bowcock, A.M., Anderson, L.A., Friedman, L.S., Black, D.M., Osborne-Lawrence, S., Rowell, S.E., Hall, J.M., Solomon, E., King, M.C. Am. J. Hum. Genet. (1993) [Pubmed]
  57. Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Ibanez de Caceres, I., Battagli, C., Esteller, M., Herman, J.G., Dulaimi, E., Edelson, M.I., Bergman, C., Ehya, H., Eisenberg, B.L., Cairns, P. Cancer Res. (2004) [Pubmed]
 
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