| Structural highlights
Disease
[BRCA1_HUMAN] Defects in BRCA1 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. Note=Mutations in BRCA1 are thought to be responsible for 45% of inherited breast cancer. Moreover, BRCA1 carriers have a 4-fold increased risk of colon cancer, whereas male carriers face a 3-fold increased risk of prostate cancer. Cells lacking BRCA1 show defects in DNA repair by homologous recombination.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] Defects in BRCA1 are a cause of susceptibility to familial breast-ovarian cancer type 1 (BROVCA1) [MIM:604370]. 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. Note=Mutations in BRCA1 are thought to be responsible for more than 80% of inherited breast-ovarian cancer. Defects in BRCA1 are a cause of susceptibility to ovarian cancer (OC) [MIM:167000]. The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Defects in BRCA1 are a cause of susceptibility to pancreatic cancer type 4 (PNCA4) [MIM:614320]. 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.
Function
[BRCA1_HUMAN] E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage. It is unclear whether it also mediates the formation of other types of polyubiquitin chains. The E3 ubiquitin-protein ligase activity is required for its tumor suppressor function. The BRCA1-BARD1 heterodimer coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Regulates centrosomal microtubule nucleation. Required for normal cell cycle progression from G2 to mitosis. Required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle. Involved in transcriptional regulation of P21 in response to DNA damage. Required for FANCD2 targeting to sites of DNA damage. May function as a transcriptional regulator. Inhibits lipid synthesis by binding to inactive phosphorylated ACACA and preventing its dephosphorylation. Contributes to homologous recombination repair (HRR) via its direct interaction with PALB2, fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Component of the BRCA1-RBBP8 complex which regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage via BRCA1-mediated ubiquitination of RBBP8.[19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The integrity of the carboxyl-terminal BRCT repeat region is critical for BRCA1 tumor suppressor function; however, the molecular details of how a number of clinically derived BRCT missense mutations affect BRCA1 function remain largely unknown. Here we assess the structural response of the BRCT tandem repeat domain to a well characterized, cancer-associated single amino acid substitution, Met-1775 --> Arg-1775. The structure of BRCT-M1775R reveals that the mutated side chain is extruded from the protein hydrophobic core, thereby altering the protein surface. Charge-charge repulsion, rearrangement of the hydrophobic core, and disruption of the native hydrogen bonding network at the interface between the two BRCT repeats contribute to the conformational instability of BRCT-M1775R. Destabilization and global unfolding of the mutated BRCT domain at physiological temperatures explain the pleiotropic molecular and genetic defects associated with the BRCA1-M1775R protein.
Structural consequences of a cancer-causing BRCA1-BRCT missense mutation.,Williams RS, Glover JN J Biol Chem. 2003 Jan 24;278(4):2630-5. Epub 2002 Nov 8. PMID:12427738[34]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Clapperton JA, Manke IA, Lowery DM, Ho T, Haire LF, Yaffe MB, Smerdon SJ. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nat Struct Mol Biol. 2004 Jun;11(6):512-8. Epub 2004 May 9. PMID:15133502 doi:10.1038/nsmb775
- ↑ Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W, et al.. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994 Oct 7;266(5182):66-71. PMID:7545954
- ↑ Williams RS, Glover JN. Structural consequences of a cancer-causing BRCA1-BRCT missense mutation. J Biol Chem. 2003 Jan 24;278(4):2630-5. Epub 2002 Nov 8. PMID:12427738 doi:10.1074/jbc.M210019200
- ↑ Tischkowitz M, Hamel N, Carvalho MA, Birrane G, Soni A, van Beers EH, Joosse SA, Wong N, Novak D, Quenneville LA, Grist SA, Nederlof PM, Goldgar DE, Tavtigian SV, Monteiro AN, Ladias JA, Foulkes WD. Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach. Eur J Hum Genet. 2008 Jul;16(7):820-32. Epub 2008 Feb 20. PMID:18285836 doi:10.1038/ejhg.2008.13
- ↑ Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S, Bennett LM, Haugen-Strano A, Swensen J, Miki Y, et al.. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994 Oct 7;266(5182):120-2. PMID:7939630
- ↑ Castilla LH, Couch FJ, Erdos MR, Hoskins KF, Calzone K, Garber JE, Boyd J, Lubin MB, Deshano ML, Brody LC, et al.. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nat Genet. 1994 Dec;8(4):387-91. PMID:7894491 doi:http://dx.doi.org/10.1038/ng1294-387
- ↑ Friedman LS, Ostermeyer EA, Szabo CI, Dowd P, Lynch ED, Rowell SE, King MC. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet. 1994 Dec;8(4):399-404. PMID:7894493 doi:http://dx.doi.org/10.1038/ng1294-399
- ↑ Serova O, Montagna M, Torchard D, Narod SA, Tonin P, Sylla B, Lynch HT, Feunteun J, Lenoir GM. A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families. Am J Hum Genet. 1996 Jan;58(1):42-51. PMID:8554067
- ↑ Durocher F, Shattuck-Eidens D, McClure M, Labrie F, Skolnick MH, Goldgar DE, Simard J. Comparison of BRCA1 polymorphisms, rare sequence variants and/or missense mutations in unaffected and breast/ovarian cancer populations. Hum Mol Genet. 1996 Jun;5(6):835-42. PMID:8776600
- ↑ Katagiri T, Emi M, Ito I, Kobayashi K, Yoshimoto M, Iwase T, Kasumi F, Miki Y, Skolnick MH, Nakamura Y. Mutations in the BRCA1 gene in Japanese breast cancer patients. Hum Mutat. 1996;7(4):334-9. PMID:8723683 doi:<334::AID-HUMU7>3.0.CO;2-8 10.1002/(SICI)1098-1004(1996)7:4<334::AID-HUMU7>3.0.CO;2-8
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- ↑ Meyer P, Voigtlaender T, Bartram CR, Klaes R. Twenty-three novel BRCA1 and BRCA2 sequence alterations in breast and/or ovarian cancer families in Southern Germany. Hum Mutat. 2003 Sep;22(3):259. PMID:12938098 doi:http://dx.doi.org/10.1002/humu.9174
- ↑ Valarmathi MT, Sawhney M, Deo SS, Shukla NK, Das SN. Novel germline mutations in the BRCA1 and BRCA2 genes in Indian breast and breast-ovarian cancer families. Hum Mutat. 2004 Feb;23(2):205. PMID:14722926 doi:10.1002/humu.9213
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- ↑ Lee JS, Collins KM, Brown AL, Lee CH, Chung JH. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature. 2000 Mar 9;404(6774):201-4. PMID:10724175 doi:10.1038/35004614
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- ↑ Vandenberg CJ, Gergely F, Ong CY, Pace P, Mallery DL, Hiom K, Patel KJ. BRCA1-independent ubiquitination of FANCD2. Mol Cell. 2003 Jul;12(1):247-54. PMID:12887909
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- ↑ Sy SM, Huen MS, Chen J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7155-60. doi:, 10.1073/pnas.0811159106. Epub 2009 Apr 15. PMID:19369211 doi:10.1073/pnas.0811159106
- ↑ Wu-Baer F, Ludwig T, Baer R. The UBXN1 protein associates with autoubiquitinated forms of the BRCA1 tumor suppressor and inhibits its enzymatic function. Mol Cell Biol. 2010 Jun;30(11):2787-98. doi: 10.1128/MCB.01056-09. Epub 2010 Mar , 29. PMID:20351172 doi:10.1128/MCB.01056-09
- ↑ Stolz A, Ertych N, Kienitz A, Vogel C, Schneider V, Fritz B, Jacob R, Dittmar G, Weichert W, Petersen I, Bastians H. The CHK2-BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells. Nat Cell Biol. 2010 May;12(5):492-9. doi: 10.1038/ncb2051. Epub 2010 Apr 4. PMID:20364141 doi:10.1038/ncb2051
- ↑ Williams RS, Glover JN. Structural consequences of a cancer-causing BRCA1-BRCT missense mutation. J Biol Chem. 2003 Jan 24;278(4):2630-5. Epub 2002 Nov 8. PMID:12427738 doi:10.1074/jbc.M210019200
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