| Structural highlights
Disease
BRCA2_HUMAN Defects in BRCA2 are a cause of susceptibility to breast cancer (BC) [MIM:114480. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] Defects in BRCA2 are the cause of pancreatic cancer type 2 (PNCA2) [MIM:613347. It is a malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue.[21] Defects in BRCA2 are a cause of susceptibility to familial breast-ovarian cancer type 2 (BROVCA2) [MIM:612555. A condition associated with familial predisposition to cancer of the breast and ovaries. Characteristic features in affected families are an early age of onset of breast cancer (often before age 50), increased chance of bilateral cancers (cancer that develop in both breasts, or both ovaries, independently), frequent occurrence of breast cancer among men, increased incidence of tumors of other specific organs, such as the prostate. Defects in BRCA2 are the cause of Fanconi anemia complementation group D type 1 (FANCD1) [MIM:605724. It is a disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair.[22] [23] [24] Defects in BRCA2 are a cause of glioma type 3 (GLM3) [MIM:613029. Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes.[25]
Function
BRCA2_HUMAN Involved in double-strand break repair and/or homologous recombination. Binds RAD51 and potentiates recombinational DNA repair by promoting assembly of RAD51 onto single-stranded DNA (ssDNA). Acts by targeting RAD51 to ssDNA over double-stranded DNA, enabling RAD51 to displace replication protein-A (RPA) from ssDNA and stabilizing RAD51-ssDNA filaments by blocking ATP hydrolysis. May participate in S phase checkpoint activation. Binds selectively to ssDNA, and to ssDNA in tailed duplexes and replication fork structures. In concert with NPM1, regulates centrosome duplication.[26] [27] [28] [29] [30] [31] [32] [33]
Publication Abstract from PubMed
Exchanges of protein sequence modules support leaps in function unavailable through point mutations during evolution. Here we study the role of the two RAD51-interacting modules within the eight binding BRC repeats of BRCA2. We created 64 chimeric repeats by shuffling these modules and measured their binding to RAD51. We found that certain shuffled module combinations were stronger binders than any of the module combinations in the natural repeats. Surprisingly, the contribution from the two modules was poorly correlated with affinities of natural repeats, with a weak BRC8 repeat containing the most effective N-terminal module. The binding of the strongest chimera, BRC8-2, to RAD51 was improved by -2.4 kCal/mol compared to the strongest natural repeat, BRC4. A crystal structure of RAD51:BRC8-2 complex shows an improved interface fit and an extended beta-hairpin in this repeat. BRC8-2 was shown to function in human cells, preventing the formation of nuclear RAD51 foci after ionizing radiation.
Improved RAD51 binders through motif shuffling based on the modularity of BRC repeats.,Lindenburg LH, Pantelejevs T, Gielen F, Zuazua-Villar P, Butz M, Rees E, Kaminski CF, Downs JA, Hyvonen M, Hollfelder F Proc Natl Acad Sci U S A. 2021 Nov 16;118(46):e2017708118. doi: , 10.1073/pnas.2017708118. PMID:34772801[34]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Kwiatkowska E, Teresiak M, Breborowicz D, Mackiewicz A. Somatic mutations in the BRCA2 gene and high frequency of allelic loss of BRCA2 in sporadic male breast cancer. Int J Cancer. 2002 Apr 20;98(6):943-5. PMID:11948477
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- ↑ Hirsch B, Shimamura A, Moreau L, Baldinger S, Hag-alshiekh M, Bostrom B, Sencer S, D'Andrea AD. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood. 2004 Apr 1;103(7):2554-9. Epub 2003 Dec 11. PMID:14670928 doi:10.1182/blood-2003-06-1970
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- ↑ Wang X, Andreassen PR, D'Andrea AD. Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin. Mol Cell Biol. 2004 Jul;24(13):5850-62. PMID:15199141 doi:10.1128/MCB.24.13.5850-5862.2004
- ↑ Ohashi A, Zdzienicka MZ, Chen J, Couch FJ. Fanconi anemia complementation group D2 (FANCD2) functions independently of BRCA2- and RAD51-associated homologous recombination in response to DNA damage. J Biol Chem. 2005 Apr 15;280(15):14877-83. Epub 2005 Jan 25. PMID:15671039 doi:M414669200
- ↑ Bahassi EM, Ovesen JL, Riesenberg AL, Bernstein WZ, Hasty PE, Stambrook PJ. The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage. Oncogene. 2008 Jun 26;27(28):3977-85. doi: 10.1038/onc.2008.17. Epub 2008 Mar 3. PMID:18317453 doi:10.1038/onc.2008.17
- ↑ Liu J, Doty T, Gibson B, Heyer WD. Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA. Nat Struct Mol Biol. 2010 Oct;17(10):1260-2. doi: 10.1038/nsmb.1904. Epub 2010, Aug 22. PMID:20729859 doi:10.1038/nsmb.1904
- ↑ Thorslund T, McIlwraith MJ, Compton SA, Lekomtsev S, Petronczki M, Griffith JD, West SC. The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA. Nat Struct Mol Biol. 2010 Oct;17(10):1263-5. doi: 10.1038/nsmb.1905. Epub 2010, Aug 22. PMID:20729858 doi:10.1038/nsmb.1905
- ↑ Jensen RB, Carreira A, Kowalczykowski SC. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature. 2010 Oct 7;467(7316):678-83. doi: 10.1038/nature09399. PMID:20729832 doi:10.1038/nature09399
- ↑ Wang HF, Takenaka K, Nakanishi A, Miki Y. BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with the Rho effector kinase ROCK2. Cancer Res. 2011 Jan 1;71(1):68-77. doi: 10.1158/0008-5472.CAN-10-0030. Epub 2010, Nov 16. PMID:21084279 doi:10.1158/0008-5472.CAN-10-0030
- ↑ Lindenburg LH, Pantelejevs T, Gielen F, Zuazua-Villar P, Butz M, Rees E, Kaminski CF, Downs JA, Hyvönen M, Hollfelder F. Improved RAD51 binders through motif shuffling based on the modularity of BRC repeats. Proc Natl Acad Sci U S A. 2021 Nov 16;118(46):e2017708118. PMID:34772801 doi:10.1073/pnas.2017708118
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