BRCA1

BRCA1

GNF_Protein_box


image_source = PDB rendering based on 1jm7.
PDB = PDB2|1jm7, PDB2|1jnx, PDB2|1n5o, PDB2|1oqa, PDB2|1t15, PDB2|1t29, PDB2|1t2u, PDB2|1t2v, PDB2|1y98
Name = Breast cancer 1, early onset
HGNCid = 1100
Symbol = BRCA1
AltSymbols =; BRCAI; BRCC1; IRIS; PSCP; RNF53
OMIM = 113705
ECnumber =
Homologene = 5276
MGIid = 104537
GeneAtlas_

GeneAtlas_

DateOfBotUpdate = 22:47, 14 September 2007 (UTC)
Function = GNF_GO|id=GO:0003674 |text = molecular_function GNF_GO|id=GO:0003677 |text = DNA binding GNF_GO|id=GO:0003684 |text = damaged DNA binding GNF_GO|id=GO:0003713 |text = transcription coactivator activity GNF_GO|id=GO:0004842 |text = ubiquitin-protein ligase activity GNF_GO|id=GO:0005515 |text = protein binding GNF_GO|id=GO:0008270 |text = zinc ion binding GNF_GO|id=GO:0015631 |text = tubulin binding GNF_GO|id=GO:0019899 |text = enzyme binding GNF_GO|id=GO:0046872 |text = metal ion binding GNF_GO|id=GO:0050681 |text = androgen receptor binding
Component = GNF_GO|id=GO:0000151 |text = ubiquitin ligase complex GNF_GO|id=GO:0000793 |text = condensed chromosome GNF_GO|id=GO:0005575 |text = cellular_component GNF_GO|id=GO:0005622 |text = intracellular GNF_GO|id=GO:0005634 |text = nucleus GNF_GO|id=GO:0005737 |text = cytoplasm GNF_GO|id=GO:0008274 |text = gamma-tubulin ring complex GNF_GO|id=GO:0031436 |text = BRCA1-BARD1 complex
Process = GNF_GO|id=GO:0000075 |text = cell cycle checkpoint GNF_GO|id=GO:0006260 |text = DNA replication GNF_GO|id=GO:0006281 |text = DNA repair GNF_GO|id=GO:0006357 |text = regulation of transcription from RNA polymerase II promoter GNF_GO|id=GO:0006359 |text = regulation of transcription from RNA polymerase III promoter GNF_GO|id=GO:0006633 |text = fatty acid biosynthetic process GNF_GO|id=GO:0006978 |text = DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator GNF_GO|id=GO:0007049 |text = cell cycle GNF_GO|id=GO:0007059 |text = chromosome segregation GNF_GO|id=GO:0007098 |text = centrosome cycle GNF_GO|id=GO:0008630 |text = DNA damage response, signal transduction resulting in induction of apoptosis GNF_GO|id=GO:0009048 |text = dosage compensation, by inactivation of X chromosome GNF_GO|id=GO:0016481 |text = negative regulation of transcription GNF_GO|id=GO:0016567 |text = protein ubiquitination GNF_GO|id=GO:0030521 |text = androgen receptor signaling pathway GNF_GO|id=GO:0031398 |text = positive regulation of protein ubiquitination GNF_GO|id=GO:0042127 |text = regulation of cell proliferation GNF_GO|id=GO:0042981 |text = regulation of apoptosis GNF_GO|id=GO:0045717 |text = negative regulation of fatty acid biosynthetic process GNF_GO|id=GO:0045739 |text = positive regulation of DNA repair GNF_GO|id=GO:0045786 |text = negative regulation of progression through cell cycle GNF_GO|id=GO:0045893 |text = positive regulation of transcription, DNA-dependent GNF_GO|id=GO:0046600 |text = negative regulation of centriole replication
Orthologs = GNF_Ortholog_box
Hs_EntrezGene = 672
Hs_Ensembl = ENSG00000012048
Hs_RefseqProtein = NP_009225
Hs_RefseqmRNA = NM_007294
Hs_GenLoc_db =
Hs_GenLoc_chr = 17
Hs_GenLoc_start = 38449840
Hs_GenLoc_end = 38530994
Hs_Uniprot = P38398
Mm_EntrezGene = 12189
Mm_Ensembl = ENSMUSG00000017146
Mm_RefseqmRNA = NM_009764
Mm_RefseqProtein = NP_033894
Mm_GenLoc_db =
Mm_GenLoc_chr = 11
Mm_GenLoc_start = 101305657
Mm_GenLoc_end = 101367902
Mm_Uniprot = Q3UMS5

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.cite web | url = http://www.pamf.org/health/guidelines/geneticscreening.html | title = Breast and Ovarian Cancer Genetic Screening | author = | authorlink = | coauthors = | date = | format = | work = | publisher = Palo Alto Medical Foundation | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-10-11] 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.cite journal| author = Starita, L.M.| coauthors = Parvin, J.D.| year = 2003| title = The multiple nuclear functions of BRCA1: transcription, ubiquitination and DNA repair| journal = Current Opinion in Cell Biology| volume = 15| issue = 3| pages = 345–350 | pmid = 12787778 | doi = 10.1016/S0955-0674(03)00042-5] 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 [http://genome.ucsc.edu/cgi-bin/hgTracks?hgsid=98579838&hgt.out1=1.5x&position=chr17%3A38449840-38530994 (map)] .

tructure

The BRCA1 protein (InterPro|IPR011364) contains the following domains:cite journal | author = Paterson JW | title = BRCA1: a review of structure and putative functions | journal = Dis. Markers | volume = 13 | issue = 4 | pages = 261–74 | year = 1998 | month = February | pmid = 9553742 | url = | issn = ]
* Zinc finger, C3HC4 type (RING finger) Pfam|PF00097
* BRCA1 C Terminus (BRCT) domain Pfam|PF00533This protein also contains nuclear localization signal and nuclear export signal motifs.cite journal | author = Henderson BR | title = Regulation of BRCA1, BRCA2 and BARD1 intracellular trafficking | journal = Bioessays | volume = 27 | issue = 9 | pages = 884–93 | year = 2005 | month = September | pmid = 16108063 | doi = 10.1002/bies.20277 | url = | issn = ]

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. [cite journal | author=S.J. Boulton | title=Cellular functions of the BRCA tumour-suppressor proteins | journal=Biochemical Society Transactions | year=2006 | pages=633–645 | volume=34 | issue=5 | pmid=17052168 | doi=10.1042/BST0340633 ] 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.cite journal| author = Paull, T.T.| coauthors = Cortez, D.; Bowers, B.; Elledge, S.J.; Gellert, M.| year = 2001| title = Direct DNA binding by Brca1| journal = Proceedings of the National Academy of Sciences| pages = 6086–6091| doi = 10.1073/pnas.111125998| volume = 98| pmid = 11353843] This may explain a role for BRCA1 to promote higher fidelity DNA repair by NHEJ.cite journal| author = Durant, S.T.| coauthors = Nickoloff, J.A.| year = 2005| title = Good timing in the cell cycle for precise DNA repair by BRCA1| journal = Cell Cycle| volume = 4| issue = 9| pages = 1216–22| url = http://www.ncbi.nlm.nih.gov/pubmed/16103751 | accessdate = 2008-05-05] 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.cite journal | author = Ye, Q. | coauthors = Hu, Y.F.; Zhong, H.; Nye, A.C.; Belmont, A.S.; Li, R. | year = 2001 | title = BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations | journal = The Journal of Cell Biology | volume = 155 | issue = 6 | pages = 911–922 | doi = 10.1083/jcb.200108049 | pmid = 11739404 ]

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.cite journal| author = Scully, R.| coauthors = Anderson, S.F.; Chao, D.M.; Wei, W.; Ye, L.; Young, R.A.; Livingston, D.M.; Parvin, J.D.| year = 1997| title = BRCA1 is a component of the RNA polymerase II holoenzyme| journal = Proceedings of the National Academy of Sciences| volume = 94| issue = 11| pages = 5605| doi = 10.1073/pnas.94.11.5605| pmid = 9159119] 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.cite journal| author = Bochar, D.A.| coauthors = Wang, L.; Beniya, H.; Kinev, A.; Xue, Y.; Lane, W.S.; Wang, W.; Kashanchi, F.; Shiekhattar, R.| year = 2000| title = BRCA1 Is Associated with a Human SWI/SNF-Related Complex Linking Chromatin Remodeling to Breast Cancer| journal = Cell| volume = 102| issue = 2| pages = 257–265| url = http://linkinghub.elsevier.com/retrieve/pii/S0092867400000301 | accessdate = 2008-05-05| doi = 10.1016/S0092-8674(00)00030-1] 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. [cite journal | author=Mazoyer S.| title=Genomic rearrangements in the BRCA1 and BRCA2 genes| journal=Hum Mutat.| year=2005 | pages=415–22| volume=25 | issue=5 | pmid=15832305 | doi=10.1002/humu.20169] Other methods are proposed: Q-PCR, [cite journal | author=Barrois M. et al | title=Real-time PCR-based gene dosage assay for detecting BRCA1 rearrangements in breast-ovarian cancer families|journal=Clin Genet.| year=2004 | pages=131–6| volume=65| issue=2 | pmid=14984472 | doi=10.1111/j.0009-9163.2004.00200.x] Multiplex Ligation-dependent Probe Amplification (MLPA), [cite journal | author=Hogervorst FB. et al | title= Large genomic deletions and duplications in the BRCA1 gene identified by a novel quantitative method|journal=Cancer Res. | year=2003 | pages=1449–53| volume=63 |issue=7 | pmid=12670888] and Quantitative Multiplex PCR of Shorts Fluorescents Fragments (QMPSF). [cite journal | author=Casilli F. et al | title= Rapid detection of novel BRCA1 rearrangements in high-risk breast-ovarian cancer families using multiplex PCR of short fluorescent fragments|journal=Hum Mutat.| year=2002 | pages=218–26| volume=20 |issue=3 | pmid=12203994 | doi=10.1002/humu.10108] 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). [cite journal | author=Rouleau E. et al | title= High-resolution oligonucleotide array-CGH applied to the detection and characterization of large rearrangements in the hereditary breast cancer gene BRCA1|journal=Clin Genet.| year=2007 | pages=199–207| volume=72| issue=3 | pmid=17718857 | doi=10.1111/j.1399-0004.2007.00849.x]

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.

ee also

* BRCA2
* Breast cancer
* Mary-Claire King

References

Further reading

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*cite book | first=Shobita| last=Parthasarathy| title=Building Genetic Medicine: Breast Cancer, Technology, and the Comparative Politics of Health Care| year=2007 | publisher=The MIT Press | id=ISBN 978-0-262-016242-5
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External links

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*cite web | url = http://egp.gs.washington.edu/data/brca1/ | title = BRCA1: breast cancer 1 | author = | authorlink = | coauthors = | date = | format = | work = NIEHS SNPs Program | publisher = National Institute of of Environmental Health Sciences | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-10-11
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