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Breast cancer type 1 susceptibility protein
Symbol(s): BRCA1
Other names: RING finger protein 53, Breast cancer 1 Early Onset, PSCP, RNF53
Genetic data
Locus: Chr. 17 q21
Protein Structure/Function
Protein length: 1863 (Amino Acids)
Molecular Weight: 207732 (Da)
Functions: DNA repair, Tumor suppressor, Transcription regulator, Centrosome dynamics
Domains: RING domain, 2 BRCT domains
Motifs: 2 NLS motifs, 2 NES motifs, CC motif
Other
Taxa expressing: Homo sapiens
Cell types: many; ovaries, testis, mammary glands, lymphocyte, prostate, cervix
Subcellular localization: Primary: Nucleus; Secondary: Cytoplasm, Centrosome
Medical/Biotechnological data
Diseases: breast-ovarian cancer (BOC) Online 'Mendelian Inheritance in Man' (OMIM) 113705
Database Links
Codes: EntrezGene 672, RefSeq NM_007295, UniProt P38398, Online 'Mendelian Inheritance in Man' (OMIM) 113705

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 Human Genome Organisation (HUGO is an organization involved in the Human Genome Project, a project about mapping the human genome Genetics (from Ancient Greek grc-Latn genetikos, “genitive” and that from grc-Latn genesis, “origin” a discipline of Biology, is In the fields of Genetics and Evolutionary computation, a locus (plural loci) is a fixed position on a Chromosome such as the position of a Chromosome 17 is one of the 23 pairs of Chromosomes in Humans People normally have two copies of this chromosome Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this The unified atomic mass unit ( u) or Dalton ( Da) or sometimes universal mass unit, is an unit of Mass used to express Deoxyribonucleic acid ( DNA) is a Nucleic acid that contains the genetic instructions used in the development and functioning of all known A tumor suppressor gene, or antioncogene is a Gene that protects a cell from one step on the path to cancer Transcription is the synthesis of RNA under the direction of DNA A protein domain is a part of protein sequence and structure that can evolve, function and exist independently of the rest of the protein chain In an unbranched chain-like biological Molecule, such as a Protein or a strand of RNA, a structural motif is a three-dimensional structural A taxon (plural taxa) or taxonomic unit, is a name designating an organism or a group of Organisms In Biological nomenclature according to Human beings, humans or man (Origin 1590–1600 L homō man OL hemō the earthly one (see Humus There are about 210 known distinct human Cell types. Keratinizing epithelial cells Epidermal Keratinocyte (differentiating "Ovaria" redirects here This is also a proposed section and a Synonym of Solanum. The testicle (from Latin testiculus, diminutive of testis, meaning "witness" virility plural testes) is the male Mammary glands are the organs that in Mammals produce Milk for the sustenance of the young A lymphocyte is a type of White blood cell in the Vertebrate Immune system. The prostate (from Greek προστάτης - prostates, literally "one who stands before" "protector" "guardian" is a The cervix (from Latin "neck" is the lower narrow portion of the Uterus where it joins with the top end of the Vagina. In Cell biology, the nucleus (pl nuclei; from Latin la ''nucleus'' or la ''nuculeus'' "little nut" or kernel is a membrane-enclosed The cytoplasm is the contents of a cell that is enclosed within the Plasma membrane. In Cell biology, the centrosome is an Organelle that serves as the main Microtubule organizing center (MTOC of the animal cell as well A disease is an abnormal condition of an organism that impairs bodily functions and can be deadly The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Entrez Global Query Cross-Database Search System is a powerful Federated search engine or Web portal that allows users to search many discrete Health sciences The National Center for Biotechnology Information ( NCBI) is part of the United States National Library of Medicine (NLM a branch of the National Institutes Swiss-Prot is a manually curated Biological database of Protein sequences The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them Human beings, humans or man (Origin 1590–1600 L homō man OL hemō the earthly one (see Humus History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance A tumor suppressor gene, or antioncogene is a Gene that protects a cell from one step on the path to cancer 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). Chromosome 17 is one of the 23 pairs of Chromosomes in Humans People normally have two copies of this chromosome In Molecular biology, two Nucleotides on opposite complementary DNA or RNA strands that are connected via Hydrogen bonds are called

Contents

Function and mechanism

DNA Damage Repair

The BRCA1 protein is directly involved in the repair of damaged DNA. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Deoxyribonucleic acid ( DNA) is a Nucleic acid that contains the genetic instructions used in the development and functioning of all known 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. RAD51 is a human Gene. The Protein encoded by this gene is a member of the RAD51 protein family which assist in repair of DNA double strand breaks. [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). A chromosome is an organized structure of DNA and Protein that is found in cells. In Biology or life science meiosis (pronounced my-oh-sis is a process of reductional division in which the number of chromosomes per cell is cut in half The BRCA2 protein, which has a function similar to that of BRCA1, also interacts with the RAD51 protein. BRCA2 (Breast Cancer Type 2 susceptibility protein is a Human Gene that is involved in the repair of chromosomal 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. Mre11-Rad50-Nbs1 (MRN is a complex of proteins involved in DNA damage repair in mammals [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. Cofactor of BRCA1, also known as COBRA1, is a human Gene that encodes NELF-B NELF (Negative elongation factor is a four subunit protein (NELF-A NELF-B NELF-C or NELF-D NELF-E that affects transcription by RNA polymerase II. [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. Breast cancer is a Cancer that starts in the cells of the Breast in women and men Researchers have identified more than 600 mutations in the BRCA1 gene, many of which are associated with an increased risk of cancer. In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism

These mutations can be changes in one or a small number of DNA base pairs (the building blocks of DNA). In Molecular biology, two Nucleotides on opposite complementary DNA or RNA strands that are connected via Hydrogen bonds are called 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] . Multiplex ligation-dependent probe amplification ( MLPA) is a variation of the Polymerase chain reaction that permits multiple targets to be amplified with only a single 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] . Comparative genomic hybridization ( CGH) or Chromosomal Microarray Analysis ( CMA) is a molecular- Cytogenetic method for the analysis of

A mutated BRCA1 gene usually makes a protein that does not function properly because it is abnormally short. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl 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. Ovarian cancer is a cancerous growth arising from an Ovary. The cancer most commonly forms in the lining of the ovary (resulting in epithelial The Fallopian tubes, also known as oviducts, uterine tubes, and salpinges ( singular salpinx) are two very fine tubes lined with ciliated Moreover, precancerous lesions (dysplasia) within the Fallopian tube have been linked to BRCA1 gene mutations. Dysplasia (from Greek roughly "bad formation" is a term used in Pathology to refer to an abnormality in maturation of cells within a tissue

See also

References

  1. ^ a b Starita, L. BRCA2 (Breast Cancer Type 2 susceptibility protein is a Human Gene that is involved in the repair of chromosomal Breast cancer is a Cancer that starts in the cells of the Breast in women and men Mary-Claire King (1946-) is an American human geneticist She is professor at the University of Washington, where she studies the Genetics and interaction of 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/S0955-0674(03)00042-5. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  2. ^ S. J. Boulton (2006). "Cellular functions of the BRCA tumour-suppressor proteins". Biochemical Society Transactions 34 (5): 633-645. PMID 17052168.  
  3. ^ 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: 6086-6091. doi:10.1073/pnas.111125998. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  4. ^ 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.  
  5. ^ 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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  6. ^ 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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  
  7. ^ 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.  
  8. ^ Mazoyer S. (2005). "Genomic rearrangements in the BRCA1 and BRCA2 genes". Hum Mutat. 25 (5): 415-22. doi:10.1002/humu.20169. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. 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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 14984472.  
  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.  
  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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 12203994.  
  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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17718857.  

Further reading

External links

The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Entrez Global Query Cross-Database Search System is a powerful Federated search engine or Web portal that allows users to search many discrete Health sciences
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