Definitions

BRCA1

BRCA1

BRCA1 (breast cancer 1, early onset) is a human gene, some mutations of which are associated with a significant increase in the risk of breast cancer, as well as other cancers. BRCA1 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. 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)

Structure

The BRCA1 protein contains the following domains:

  • Zinc finger, C3HC4 type (RING finger)
  • BRCA1 C Terminus (BRCT) domain

This protein also contains nuclear localization signal and nuclear export signal motifs.

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. 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. This may explain a role for BRCA1 to promote higher fidelity DNA repair by NHEJ. 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.

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. 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. 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. BRCA1 interacts with the NELF-B (COBRA1) subunit of the NELF complex.

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. Other methods are proposed: Q-PCR, Multiplex Ligation-dependent Probe Amplification (MLPA), and Quantitative Multiplex PCR of Shorts Fluorescents Fragments (QMPSF). 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).

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

Further reading

  • Cui JQ, Wang H, Reddy ES, Rao VN (1998). "Differential transcriptional activation by the N-terminal region of BRCA1 splice variants BRCA1a and BRCA1b". Oncology reports 5 (3): 585–9.
  • Wang H, Shao N, Ding QM, Cui J, Reddy ES, Rao VN (1997). "BRCA1 proteins are transported to the nucleus in the absence of serum and splice variants BRCA1a, BRCA1b are tyrosine phosphoproteins that associate with E2F, cyclins and cyclin dependent kinases". Oncogene 15 (2): 143–57.
  • Cui JQ, Wang H, Reddy ES, Rao VN (1998). "Differential transcriptional activation by the N-terminal region of BRCA1 splice variants BRCA1a and BRCA1b". Oncology reports 5 (3): 585–9.
  • Cui JQ, Shao N, Chai Y, Wang H, Reddy ES, Rao VN (1998). "BRCA1 splice variants BRCA1a and BRCA1b associate with CBP co-activator". Oncology reports 5 (3): 591–5.
  • 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.
  • 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.
  • Barnett GL, Friedrich CA (2004). "Recent developments in ovarian cancer genetics". Curr Opin Obstet Gynecol 16 (1): 79–85.
  • 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.
  • Daniel DC (2002). "Highlight: BRCA1 and BRCA2 proteins in breast cancer". Microsc Res Tech 59 (1): 68–83.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Scully R, Puget N (2002). "BRCA1 and BRCA2 in hereditary breast cancer". Biochimie 84 (1): 95–102.
  • 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.
  • Venkitaraman AR (2002). "Cancer susceptibility and the functions of BRCA1 and BRCA2". Cell 108 (2): 171–82.
  • 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.

External links

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