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14-September-2008 11:27:24 - BRCA1 Breast cancer 1, early onset PDB rendering based on 1jm7. Available structures: 1jm7, 1jnx, 1n5o, 1oqa, 1t15, 1t29, 1t2u, 1t2v, 1y98 Identifiers Symbols BRCA1; BRCAI; BRCC1; IRIS; PSCP; RNF53 External IDs OMIM: 113705 MGI: 104537 HomoloGene: 5276 Gene ontology Molecular function: molecular_function DNA binding damaged DNA binding transcription coactivator activity ubiquitin-protein ligase activity protein binding zinc ion binding tubulin binding enzyme binding metal ion binding androgen receptor binding Cellular component: ubiquitin ligase complex condensed chromosome cellular_component intracellular nucleus cytoplasm gamma-tubulin ring complex BRCA1-BARD1 complex Biological process: cell cycle checkpoint DNA replication DNA repair regulation of transcription from RNA polymerase II promoter regulation of transcription from RNA polymerase III promoter fatty acid biosynthetic process DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator cell cycle chromosome segregation centrosome cycle DNA damage response, signal transduction resulting in induction of apoptosis dosage compensation, by inactivation of X chromosome negative regulation of transcription protein ubiquitination androgen receptor signaling pathway positive regulation of protein ubiquitination regulation of cell proliferation regulation of apoptosis negative regulation of fatty acid biosynthetic process positive regulation of DNA repair negative regulation of progression through cell cycle positive regulation of transcription, DNA-dependent negative regulation of centriole replication RNA expression pattern More reference expression data Orthologs Human Mouse Entrez 672 12189 Ensembl ENSG00000012048 ENSMUSG00000017146 Uniprot P38398 Q3UMS5 Refseq NM_007294 mRNA NP_009225 protein NM_009764 mRNA NP_033894 protein Location Chr 17: 38.45 - 38.53 Mb Chr 11: 101.31 - 101.37 Mb Pubmed search 1 2 BRCA1 breast cancer 1, early onset is a human gene that belongs to a class of genes known as tumor suppressors, which maintains genomic integrity to prevent uncontrolled proliferation. The multifactorial BRCA1 protein product is involved in DNA damage repair, ubiquitination, transcriptional regulation as well as other functions.1 Variations in the gene have been implicated in a number of herary cancers, namely breast, ovarian and prostate. The BRCA1 gene is located on the long q arm of chromosome 17 at band 21, from base pair 38,449,843 to base pair 38,530,933 map. Contents 1 Structure 2 Function and mechanism 2.1 DNA Damage Repair 2.2 Transcription 2.3 Other roles 3 Mutations Cancer Risk 4 See also 5 References 6 Further reading 7 External links Structure The BRCA1 protein IPR011364 contains the following domains:2 Zinc finger, C3HC4 type RING finger Pfam PF00097 BRCA1 C Terminus BRCT domain Pfam PF00533 This protein also contains nuclear localization signal and nuclear export signal motifs.3 Function and mechanism DNA Damage Repair The BRCA1 protein is directly involved in the repair of damaged DNA. In the nucleus of many types of normal cells, the BRCA1 protein is thought to interact with RAD51 during repair of DNA double-strand breaks, though the details and significance of this interaction is the subject of debate.4 These breaks can be caused by natural radiation or other exposures, but also occur when chromosomes exchange genetic material during a special type of cell division that creates sperm and eggs meiosis. The BRCA2 protein, which has a function similar to that of BRCA1, also interacts with the RAD51 protein. By influencing DNA damage repair, these three proteins play a role in maintaining the stability of the human genome. BRCA1 directly binds to DNA, with higher affinity for branched DNA structures. This ability to bind to DNA contributes to its ability to inhibit the nuclease activity of the MRN complex as well as the nuclease activity of Mre11 alone.5 This may explain a role for BRCA1 to promote higher fidelity DNA repair by NHEJ.6 BRCA1 also colocalizes with γ-H2AX histone H2AX phosphorylated on serine-139 in DNA double-strand break repair foci, indicating it may play a role in recruiting repair factors.71 Transcription BRCA1 was shown to co-purify with the human RNA Polymerase II holoenzyme in HeLa extracts, implying it is a component of the holoenzyme.8 Later research, however, contradicted this assumption, instead showing that the predominant complex including BRCA1 in HeLa cells is a 2 megadalton complex containing SWI/SNF.9 SWI/SNF is a chromatin remodeling complex. Artificial tethering of BRCA1 to chromatin was shown to decondense heterochromatin, though the SWI/SNF interacting domain was not necessary for this role.7 BRCA1 interacts with the NELF-B COBRA1 subunit of the NELF complex.7 Other roles Research suggests that both the BRCA1 and BRCA2 proteins regulate the activity of other genes and play a critical role in embryo development. The BRCA1 protein probably interacts with many other proteins, including tumor suppressors and regulators of the cell division cycle. Mutations Cancer Risk Certain variations of the BRCA1 gene lead to an increased risk for breast cancer. Researchers have identified more than 600 mutations in the BRCA1 gene, many of which are associated with an increased risk of cancer. These mutations can be changes in one or a small number of DNA base pairs the building blocks of DNA. Those mutations can be identified with PCR and DNA sequencing. In some cases, large segments of DNA are rearranged. Those large segments, also called large rearrangements, can be a deletion or a duplication of one or several exons in the gene. Classical methods for mutations detectionsequencing are unable to reveal those mutations.10. Other methods are proposed : Q-PCR11, Multiplex Ligation-dependent Probe Amplification MLPA12 , and Quantitative Multiplex PCR of Shorts Fluorescents Fragments QMPSF13 . New methods have been recently proposed : heteroduplex analysis HDA by multi-capillary electrophoresis or also dedicated oligonucleotides array based on comparative genomic hybridization array-CGH14 . A mutated BRCA1 gene usually makes a protein that does not function properly because it is abnormally short. Researchers believe that the defective BRCA1 protein is unable to help fix mutations that occur in other genes. These defects accumulate and may allow cells to grow and divide uncontrollably to form a tumor. In addition to breast cancer, mutations in the BRCA1 gene also increase the risk on ovarian, Fallopian tube and prostate cancers. Moreover, precancerous lesions dysplasia within the Fallopian tube have been linked to BRCA1 gene mutations. See also BRCA2 Breast cancer Mary-Claire King References ^ a b Starita, L.M.; Parvin, J.D. 2003. The multiple nuclear functions of BRCA1: transcription, ubiquitination and DNA repair. Current Opinion in Cell Biology 15 3: 345-350. doi:10.1016/S0955-06740300042-5. ^ Paterson JW February 1998. BRCA1: a review of structure and putative functions. Dis. Markers 13 4: 261-74. PMID 9553742. ^ Henderson BR September 2005. Regulation of BRCA1, BRCA2 and BARD1 intracellular trafficking. Bioessays 27 9: 884-93. doi:10.1002/bies.20277. PMID 16108063. ^ S.J. Boulton 2006. Cellular functions of the BRCA tumour-suppressor proteins. Biochemical Society Transactions 34 5: 633-645. doi:10.1042/BST0340633. PMID 17052168. ^ Paull, T.T.; Cortez, D.; Bowers, B.; Elledge, S.J.; Gellert, M. 2001. Direct DNA binding by Brca1. Proceedings of the National Academy of Sciences 98: 6086-6091. doi:10.1073/pnas.111125998. PMID 11353843. ^ Durant, S.T.; Nickoloff, J.A. 2005. Good timing in the cell cycle for precise DNA repair by BRCA1. Cell Cycle 4 9: 1216-22. Retrieved on 2008-05-05. ^ a b c Ye, Q.; Hu, Y.F.; Zhong, H.; Nye, A.C.; Belmont, A.S.; Li, R. 2001. BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations. The Journal of Cell Biology 155 6: 911-922. doi:10.1083/jcb.200108049. PMID 11739404. ^ Scully, R.; Anderson, S.F.; Chao, D.M.; Wei, W.; Ye, L.; Young, R.A.; Livingston, D.M.; Parvin, J.D. 1997. BRCA1 is a component of the RNA polymerase II holoenzyme. Proceedings of the National Academy of Sciences 94 11: 5605. doi:10.1073/pnas.94.11.5605. PMID 9159119. ^ Bochar, D.A.; Wang, L.; Beniya, H.; Kinev, A.; Xue, Y.; Lane, W.S.; Wang, W.; Kashanchi, F.; Shiekhattar, R. 2000. BRCA1 Is Associated with a Human SWI/SNF-Related Complex Linking Chromatin Remodeling to Breast Cancer. Cell 102 2: 257-265. doi:10.1016/S0092-86740000030-1. Retrieved on 2008-05-05. ^ Mazoyer S. 2005. Genomic rearrangements in the BRCA1 and BRCA2 genes. Hum Mutat. 25 5: 415-22. doi:10.1002/humu.20169. PMID 15832305. ^ Barrois M. et al 2004. Real-time PCR-based gene dosage assay for detecting BRCA1 rearrangements in breast-ovarian cancer families. Clin Genet. 65 2: 131-6. doi:10.1111/j.0009-9163.2004.00200.x. PMID 14984472. ^ Hogervorst FB. et al 2003. Large genomic deletions and duplications in the BRCA1 gene identified by a novel quantitative method. Cancer Res. 63 7: 1449-53. PMID 12670888. ^ Casilli F. et al 2002. Rapid detection of novel BRCA1 rearrangements in high-risk breast-ovarian cancer families using multiplex PCR of short fluorescent fragments. Hum Mutat. 20 3: 218-26. doi:10.1002/humu.10108. PMID 12203994. ^ Rouleau E. et al 2007. High-resolution oligonucleotide array-CGH applied to the detection and characterization of large rearrangements in the herary breast cancer gene BRCA1. Clin Genet. 72 3: 199-207. doi:10.1111/j.1399-0004.2007.00849.x. PMID 17718857. Further reading Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B, Tulinius H, Thorlacius S, Eerola H, Nevanlinna H, Syrjakoski K, Kallioniemi OP, Thompson D, Evans C, Peto J, Lalloo F, Evans DG, Easton DF 2003. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72 5: 1117-30. doi:10.1086/375033. PMID 12677558. Barnett GL, Friedrich CA 2004. Recent developments in ovarian cancer genetics. Curr Opin Obstet Gynecol 16 1: 79-85. doi:10.1097/00001703-200402000-00014. PMID 15128012. Botuyan MV, Nomine Y, Xu Y, Juranic N, Macura S, Chen J, Mer G 2004. Structural basis of BACH1 phosphopeptide recognition by BRCA1 tandem BRCT domains. Structure 12 7: 1137-1146. doi:10.1016/j.str.2004.06.002. PMID 15242590. 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. Ding SL, Sheu LF, Yu JC, Yang TL, Chen BF, Leu FJ, Shen CY 2004. Abnormality of the DNA double-strand-break checkpoint/repair genes, ATM, BRCA1 and TP53, in breast cancer is related to tumour grade. Br J Cancer 90 10: 1995-2001. doi:10.1038/sj.bjc.6601804. PMID 15138484. Foulkes WD, Metcalfe K, Sun P, Hanna WM, Lynch HT, Ghadirian P, Tung N, Olopade OI, Weber BL, McLennan J, Olivotto IA, Begin LR, Narod SA 2004. Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type. Clin Cancer Res 10 6: 2029-34. doi:10.1158/1078-0432.CCR-03-1061. PMID 15041722. Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King MC 1990. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250 4988: 1684-89. doi:10.1126/science.2270482. PMID 2270482. Liede A, Karlan BY, Narod SA 2004. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 22 4: 735-42. doi:10.1200/JCO.2004.05.055. PMID 14966099. Metcalfe K, Lynch HT, Ghadirian P, Tung N, Olivotto I, Warner E, Olopade OI, Eisen A, Weber B, McLennan J, Sun P, Foulkes WD, Narod SA 2004. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 22 12: 2328-35. doi:10.1200/JCO.2004.04.033. PMID 15197194. Parthasarathy, Shobita 2007. Building Genetic Medicine: Breast Cancer, Technology, and the Comparative Politics of Health Care. The MIT Press. ISBN 978-0-262-016242-5. Powell SN, Kachnic LA 2003. Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene 22 37: 5784-91. doi:10.1038/sj.onc.1206678. PMID 12947386. Scully R, Puget N 2002. BRCA1 and BRCA2 in herary breast cancer. Biochimie 84 1: 95-102. doi:10.1016/S0300-90840101359-1. PMID 11900881. Tutt A, Ashworth A 2002. The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol Med 8 12: 571-6. doi:10.1016/S1471-49140202434-6. PMID 12470990. Venkitaraman AR 2002. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108 2: 171-82. doi:10.1016/S0092-86740200615-3. PMID 11832208. Zweemer RP, van Diest PJ, Verheijen RH, Ryan A, Gille JJ, Sijmons RH, Jacobs IJ, Menko FH, Kenemans P 2000. Molecular evidence linking primary cancer of the fallopian tube to BRCA1 germline mutations. gynecol oncol 76 1: 45. doi:10.1006/gyno.1999.5623. PMID 10620440. Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, Gille JJ, Jongsma AP, Pals G, Kenemans P, Verheijen RH 2001. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol. 195 4: 451. doi:10.1002/path.1000. PMID 11745677. External links Cancer.gov NIEHS MeSH BRCA1+Protein MeSH Genes,+BRCA1 v d e Neoplasm: Tumor suppressor genes/proteins Cell membrane MAPK/ERK pathway Neurofibromin 1 Wnt signaling pathway CDH1 Hedgehog signaling pathway PTCH1 TGF beta signaling pathway TGF beta receptor 2 other/unknown Maspin Cytosol/cytoskeleton Wnt signaling pathway APC TGF beta signaling pathway SMAD2, SMAD4 Akt/PKB signaling pathway PTEN other/unknown: Neurofibromin 2/Merlin Mitochondria SDHB - SDHD Nucleus Cell cycle regulation: pRb - CHEK2 - p14arf/p16 - cip/kip p21, p27, p57 - p53 p63 p73 family p53, p63, p73 - WT1 DNA repair/Fanconi: BRCA1 - BRCA2 other: KLF6 - VHL see also oncogenes Retrieved from http://en..org/wiki/BRCA1 Categories: Genes on chromosome 17 | Human proteins | Tumor markers | Tumor suppressor genes Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Català Deutsch Español Français Italiano Polski Português اردو This page was last modified on 7 September 2008, at 15:08
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