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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, some mutations of which are associated with a significant increase in the risk of breast cancer, as well as other cancers.¹ 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.² 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:³

• 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.⁴

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.⁵ These breaks can be caused by natural radiation or other exposures, but also occur when chromosomes exchange genetic material (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.⁶ This may explain a role for BRCA1 to promote higher fidelity DNA repair by NHEJ.⁷ 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.⁸²

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.⁹ 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.¹⁰ 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.⁸ BRCA1 interacts with the NELF-B (COBRA1) subunit of the NELF complex.⁸

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.¹¹ Other methods are proposed: Q-PCR,¹² Multiplex Ligation-dependent Probe Amplification (MLPA),¹³ and Quantitative Multiplex PCR of Shorts Fluorescents Fragments (QMPSF).¹⁴ 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).¹⁵

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

Further reading

External links

• MeSH BRCA1 Protein
• MeSH Genes, BRCA1
• "Genetic Testing for BRCA1 and BRCA2 - National Cancer Institute". National Cancer Institute. Retrieved on 2008-10-11.
• "BRCA1: breast cancer 1". NIEHS SNPs Program. National Institute of of Environmental Health Sciences. Retrieved on 2008-10-11.
• "FORCE: Facing Our Risk of Cancer Empowered -- Hereditary, Genetic Breast or Ovarian Cancer and BRCA Issues". Facing Our Risk of Cancer Empowered, Inc.. Retrieved on 2008-10-11.

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

Wikipedia content modification information:

• This page was last modified on 25 October 2008, at 18:06.

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