BRCA2

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BRCA2
Properties of human protein
Mass / length primary structure 3418 amino acids
Identifier
Gene name BRCA2
External IDs
Occurrence
Parent taxon Eukaryotes

Ribbon model of the complex of RAD51 (amino acids 97-339) and the fourth BRCA2 domain (amino acids 1517-1551), according to PDB 1N0W .

BRCA2 is a protein in the cell nuclei of most eukaryotes that, as a subunit of several protein complexes, plays a key role in DNA repair and homologous recombination . In humans, BRCA2 is mainly produced in the mammary and thymus glands , as well as in the lungs , ovaries and spleen . Homozygous mutations in BRCA2 - gene are for increased risk of pancreatic cancer, breast and ovarian cancer in charge. The gene is therefore included in the (outdated) class of tumor suppressor genes .

Surname

BRCA2 is an abbreviation for the English expression BR east CA ncer 2 , early-onset ( German : breast cancer 2, early manifestation), in some publications the gene is also referred to as breast cancer gene 2 .

Gene localization

The BRCA2 gene is located on the long arm (q arm) of chromosome 13 , gene locus 12.3. It ranges from base pair 31,787,616 to base pair 31,871,804, that is, it comprises 84,193 base pairs. The protein encoded from it consists of 3418 amino acids and has a molar mass of 384,225  Da .

Biological function

The BRCA2 protein binds to RAD51 and PALB2. The complex with RAD51 binds to DNA double-strand breaks with the help of PALB2 and initiates DNA repair. BRCA2 is required for the formation of the RAD51 nucleofilaments by removing RPA from the resected DNA segment and replacing it with Rad51. BRCA2 is also required to repair strand breaks in meiotic and mitotic cell division . BRCA2 is therefore essential for the genetic stability of a eukaryotic cell.

A complete loss of function of both BRCA2 genes in the germ cells leads to death in the early embryonic stage. Mutations with little residual activity lead to Fanconi anemia group D type 1 with chromosomal instability ( chromosome break syndrome ) and often with developmental disorders such as microcephaly , short stature , bone malformations, abnormal skin pigmentation (especially café-au-lait spots ), premature bone marrow failure ( myelosuppression ) and a high risk of solid tumors and acute myeloid leukemia . Few children experience growing up.

In addition, BRCA2 plays a role in oogenesis, the development of the ovaries . Since double-strand breaks must also be repaired in meiosis , which is inhibited in the event of partial loss of the BRCA2 function, in animal models and in mutations with reduced BRCA2 function, decreased oocytes and an early depletion of the ovaries, up to and including an absence of ovaries, are found a sterility. Genital malformations, gonadal hypoplasia and sterility have also been described in men .

Risk and Detection

Women and men with a germline mutation in BRCA2 have an increased risk of developing breast or ovarian cancer, as well as other types of cancer.

A DNA analysis can be used to determine whether a patient has a mutated form of the BRCA2 gene. For women and men with a family history of breast and ovarian cancer, the statutory health insurance companies cover the costs of advice, genetic testing and the early detection program. Performing the test is considered useful if one of the following criteria applies:

  • at least two people in the family have or have had breast cancer, at least one of them before the age of 51
  • three people with breast cancer in the family (regardless of age)
  • a family disease with unilateral breast cancer and an age of onset before the age of 36
  • a family history of bilateral breast cancer with the first disease occurring at age 50 or earlier
  • a family history of ovarian cancer if the disease started before the age of 41
  • a family case with breast and ovarian cancer
  • breast cancer in a man
  • two or more cases of ovarian cancer in the family.

Before and after performing the genetic test, it is very important to have intensive discussions with the patient.

discovery

The BRCA2 gene was 1994 by Michael Stratton and Richard Wooster at Institute of Cancer Research of the University of London discovered.

Prevention

See also

literature

  • E. Honrado et al. a .: Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations. In: Oncogene , 25/2006, pp. 5837-45. PMID 16998498
  • SM Domchek, BL Weber: Clinical management of BRCA1 and BRCA2 mutation carriers. In: Oncogene , 25/2006, pp. 5825-31. PMID 16998496
  • T. Hay, AR Clarke: DNA damage hypersensitivity in cells lacking BRCA2: a review of in vitro and in vivo data. In: Biochem Soc Trans , 33/2005, pp. 715-7. PMID 16042582
  • A. Tutt, A. Ashworth: The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. In: Trends Mol Med , 8/2002, pp. 571-6. PMID 12470990
  • DC Daniel: Highlight: BRCA1 and BRCA2 proteins in breast cancer. In: Microsc Res Tech , 59/2002, pp. 68-83. PMID 12242698
  • BJ Orelli, DK Bishop: BRCA2 and homologous recombination. In: Breast Cancer Res , 3/2001, pp. 294-8. PMID 11597317
  • AR Venkitaraman: Chromosome stability, DNA recombination and the BRCA2 tumor suppressor. In: Curr Opin Cell Biol , 13/2001, pp. 338-43. PMID 11343905

Web links

Individual evidence

  1. ↑ UniProt search result with PS50138 Match by taxonomy
  2. ↑ UniProt P51587
  3. ↑ Thorslund T, West SC: BRCA2: a universal recombinase regulator . In: Oncogene . 26, No. 56, December 2007, pp. 7720-30. doi : 10.1038 / sj.onc.1210870 . PMID 18066084 .
  4. ↑ a b Ariella Weinberg-Shukron, Mariana Rachmiel, Paul Renbaum, Suleyman Gulsuner, Tom Walsh, Orit Lobel, Amatzia Dreifuss, Avital Ben-Moshe, Sharon Zeligson, Reeval Segel, Tikva Shore, Rachel Kalifa, Michal Goldberg, Mary-Claire King , Offer Gerlitz, Ephrat Levy-Lahad, David Zangen et al .: Essential Role of BRCA2 in Ovarian Development and Function . New England Journal of Medicine 2018, Volume 379, Issue 11, September 13, 2018, pages 1042-1049, DOI: 10.1056 / NEJMoa1800024
  5. ↑ Ute Hamann: Breast cancer - is it the genes or the environment? GSF Research Center for Environment and Health, Neuherberg 2003, DNB  970082770 , urn : nbn: de: 101: 1-200911022939 .
  6. ↑ K. Ullrich: BRCA1 / 2 testing: criteria were modified. In: Medical Tribune . No. 2, April 2008, p. 7.
  7. ^ H. Keßler: Breast cancer: early detection by genetic test - redemption or stroke of fate: how a genetic test changes the life of women . In: Die Zeit , No. 12/1996
  8. ↑ Beckmann MW, High-Risk Families with Breast and Ovarian Cancer: Options for Counseling, Genetic Analysis and Early Detection , in Deutsches Ärzteblatt , 94/1997, pp. A161–167.
  9. ↑ MR Stratton et al. a .: Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q. In: Nat Genet . , 7/1994, pp. 103-7. PMID 8075631
  10. ^ MR Stratton, R. Wooster: Hereditary predisposition to breast cancer. In: Curr Opin Genet Dev , 6/1996, pp. 93-7. PMID 8791478