BRCA1

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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 hereditary 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).

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.[2] 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.[3] This may explain a role for BRCA1 to promote higher fidelity DNA repair by NHEJ.[4] 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.[5][1]

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.[6] 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.[7] 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.[5] BRCA1 interacts with the NELF-B (COBRA1) subunit of the NELF complex.[5]

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 detection(sequencing) are unable to reveal those mutations.[8]. Other methods are proposed : Q-PCR[9], Multiplex Ligation-dependent Probe Amplification (MLPA)[10] , and Quantitative Multiplex PCR of Shorts Fluorescents Fragments (QMPSF)[11] . New methods have been recently proposed : heteroduplex analysis (HDA) by multi-capillary electrophoresis or also dedicated oligonucleotides array based on comparative genomic hybridization (array-CGH)[12] .

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

References

  1. ^ a b Starita, L.M. (2003). "The multiple nuclear functions of BRCA1: transcription, ubiquitination and DNA repair". Current Opinion in Cell Biology. 15 (3): 345–350. doi:10.1016/S0955-0674(03)00042-5. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  2. ^ 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.
  3. ^ Paull, T.T. (2001). "Direct DNA binding by Brca1". Proceedings of the National Academy of Sciences. 98: 6086–6091. doi:10.1073/pnas.111125998. PMID 11353843. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  4. ^ Durant, S.T. (2005). "Good timing in the cell cycle for precise DNA repair by BRCA1". Cell Cycle. 4 (9): 1216–22. Retrieved 2008-05-05. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. ^ a b c Ye, Q. (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. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ Scully, R. (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. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ Bochar, D.A. (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/S0092-8674(00)00030-1. Retrieved 2008-05-05. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  8. ^ Mazoyer S. (2005). "Genomic rearrangements in the BRCA1 and BRCA2 genes". Hum Mutat. 25 (5): 415–22. doi:10.1002/humu.20169. PMID 15832305.
  9. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)
  10. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)
  11. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)
  12. ^ Rouleau E.; et al. (2007). "High-resolution oligonucleotide array-CGH applied to the detection and characterization of large rearrangements in the hereditary breast cancer gene BRCA1". Clin Genet. 72 (3): 199–207. doi:10.1111/j.1399-0004.2007.00849.x. PMID 17718857. {{cite journal}}: Explicit use of et al. in: |author= (help)

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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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.
  • 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • 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 hereditary breast cancer". Biochimie. 84 (1): 95–102. doi:10.1016/S0300-9084(01)01359-1. 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/S1471-4914(02)02434-6. PMID 12470990.
  • Venkitaraman AR (2002). "Cancer susceptibility and the functions of BRCA1 and BRCA2". Cell. 108 (2): 171–82. doi:10.1016/S0092-8674(02)00615-3. 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. {{cite journal}}: Cite has empty unknown parameter: |unused_data= (help); Text "pages45-50" ignored (help)CS1 maint: multiple names: authors list (link)
  • 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. {{cite journal}}: Cite has empty unknown parameter: |unused_data= (help); Text "pages451-56" ignored (help)CS1 maint: multiple names: authors list (link)

External links

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