4y2g

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]} [F175A_HUMAN] Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX. In the BRCA1-A complex, it acts as a central scaffold protein that assembles the various components of the BRCA1-A complex and mediates the recruitment of BRCA1.^{[34] [35] [36] [37] [38]}

References

1. ↑ Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, Grossman S, Wahrer DC, Sgroi DC, Lane WS, Haber DA, Livingston DM. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell. 2001 Apr 6;105(1):149-60. PMID:11301010
2. ↑ 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
3. ↑ 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
4. ↑ 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
5. ↑ 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
6. ↑ 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
7. ↑ 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
8. ↑ 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
9. ↑ 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
10. ↑ 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
11. ↑ 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
12. ↑ Dong J, Chang-Claude J, Wu Y, Schumacher V, Debatin I, Tonin P, Royer-Pokora B. A high proportion of mutations in the BRCA1 gene in German breast/ovarian cancer families with clustering of mutations in the 3' third of the gene. Hum Genet. 1998 Aug;103(2):154-61. PMID:9760198
13. ↑ Andersen TI, Eiken HG, Couch F, Kaada G, Skrede M, Johnsen H, Aloysius TA, Tveit KM, Tranebjaerg L, Dorum A, Moller P, Weber BL, Borresen-Dale AL. Constant denaturant gel electrophoresis (CDGE) in BRCA1 mutation screening. Hum Mutat. 1998;11(2):166-74. PMID:9482581 doi:<166::AID-HUMU10>3.0.CO;2-X 10.1002/(SICI)1098-1004(1998)11:2<166::AID-HUMU10>3.0.CO;2-X
14. ↑ Katagiri T, Kasumi F, Yoshimoto M, Nomizu T, Asaishi K, Abe R, Tsuchiya A, Sugano M, Takai S, Yoneda M, Fukutomi T, Nanba K, Makita M, Okazaki H, Hirata K, Okazaki M, Furutsuma Y, Morishita Y, Iino Y, Karino T, Ayabe H, Hara S, Kajiwara T, Houga S, Miki Y, et al.. High proportion of missense mutations of the BRCA1 and BRCA2 genes in Japanese breast cancer families. J Hum Genet. 1998;43(1):42-8. PMID:9609997 doi:10.1007/s100380050035
15. ↑ Li SS, Tseng HM, Yang TP, Liu CH, Teng SJ, Huang HW, Chen LM, Kao HW, Chen JH, Tseng JN, Chen A, Hou MF, Huang TJ, Chang HT, Mok KT, Tsai JH. Molecular characterization of germline mutations in the BRCA1 and BRCA2 genes from breast cancer families in Taiwan. Hum Genet. 1999 Mar;104(3):201-4. PMID:10323242
16. ↑ Ruiz-Flores P, Sinilnikova OM, Badzioch M, Calderon-Garciduenas AL, Chopin S, Fabrice O, Gonzalez-Guerrero JF, Szabo C, Lenoir G, Goldgar DE, Barrera-Saldana HA. BRCA1 and BRCA2 mutation analysis of early-onset and familial breast cancer cases in Mexico. Hum Mutat. 2002 Dec;20(6):474-5. PMID:12442275 doi:10.1002/humu.9084
17. ↑ 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
18. ↑ 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
19. ↑ Lorick KL, Jensen JP, Fang S, Ong AM, Hatakeyama S, Weissman AM. RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11364-9. PMID:10500182
20. ↑ 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
21. ↑ Yarden RI, Pardo-Reoyo S, Sgagias M, Cowan KH, Brody LC. BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nat Genet. 2002 Mar;30(3):285-9. Epub 2002 Feb 11. PMID:11836499 doi:10.1038/ng837
22. ↑ Wu-Baer F, Lagrazon K, Yuan W, Baer R. The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin. J Biol Chem. 2003 Sep 12;278(37):34743-6. Epub 2003 Jul 30. PMID:12890688 doi:10.1074/jbc.C300249200
23. ↑ 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
24. ↑ Morris JR, Solomon E. BRCA1 : BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair. Hum Mol Genet. 2004 Apr 15;13(8):807-17. Epub 2004 Feb 19. PMID:14976165 doi:10.1093/hmg/ddh095
25. ↑ Ouchi M, Fujiuchi N, Sasai K, Katayama H, Minamishima YA, Ongusaha PP, Deng C, Sen S, Lee SW, Ouchi T. BRCA1 phosphorylation by Aurora-A in the regulation of G2 to M transition. J Biol Chem. 2004 May 7;279(19):19643-8. Epub 2004 Feb 27. PMID:14990569 doi:10.1074/jbc.M311780200
26. ↑ Yu X, Fu S, Lai M, Baer R, Chen J. BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev. 2006 Jul 1;20(13):1721-6. PMID:16818604 doi:10.1101/gad.1431006
27. ↑ Moreau K, Dizin E, Ray H, Luquain C, Lefai E, Foufelle F, Billaud M, Lenoir GM, Venezia ND. BRCA1 affects lipid synthesis through its interaction with acetyl-CoA carboxylase. J Biol Chem. 2006 Feb 10;281(6):3172-81. Epub 2005 Dec 2. PMID:16326698 doi:10.1074/jbc.M504652200
28. ↑ Sankaran S, Crone DE, Palazzo RE, Parvin JD. Aurora-A kinase regulates breast cancer associated gene 1 inhibition of centrosome-dependent microtubule nucleation. Cancer Res. 2007 Dec 1;67(23):11186-94. PMID:18056443 doi:10.1158/0008-5472.CAN-07-2578
29. ↑ Wang B, Matsuoka S, Ballif BA, Zhang D, Smogorzewska A, Gygi SP, Elledge SJ. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science. 2007 May 25;316(5828):1194-8. PMID:17525340 doi:10.1126/science.1139476
30. ↑ Feng L, Huang J, Chen J. MERIT40 facilitates BRCA1 localization and DNA damage repair. Genes Dev. 2009 Mar 15;23(6):719-28. doi: 10.1101/gad.1770609. Epub 2009 Mar 4. PMID:19261748 doi:10.1101/gad.1770609
31. ↑ 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
32. ↑ 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
33. ↑ 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
34. ↑ Wang B, Matsuoka S, Ballif BA, Zhang D, Smogorzewska A, Gygi SP, Elledge SJ. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science. 2007 May 25;316(5828):1194-8. PMID:17525340 doi:10.1126/science.1139476
35. ↑ Liu Z, Wu J, Yu X. CCDC98 targets BRCA1 to DNA damage sites. Nat Struct Mol Biol. 2007 Aug;14(8):716-20. Epub 2007 Jul 22. PMID:17643121 doi:http://dx.doi.org/nsmb1279
36. ↑ Kim H, Huang J, Chen J. CCDC98 is a BRCA1-BRCT domain-binding protein involved in the DNA damage response. Nat Struct Mol Biol. 2007 Aug;14(8):710-5. Epub 2007 Jul 22. PMID:17643122 doi:http://dx.doi.org/nsmb1277
37. ↑ Wang B, Elledge SJ. Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20759-63. Epub 2007 Dec 5. PMID:18077395 doi:http://dx.doi.org/0710061104
38. ↑ Feng L, Huang J, Chen J. MERIT40 facilitates BRCA1 localization and DNA damage repair. Genes Dev. 2009 Mar 15;23(6):719-28. doi: 10.1101/gad.1770609. Epub 2009 Mar 4. PMID:19261748 doi:10.1101/gad.1770609
39. ↑ Wu Q, Paul A, Su D, Mehmood S, Foo TK, Ochi T, Bunting EL, Xia B, Robinson CV, Wang B, Blundell TL. Structure of BRCA1-BRCT/Abraxas Complex Reveals Phosphorylation-Dependent BRCT Dimerization at DNA Damage Sites. Mol Cell. 2016 Jan 13. pii: S1097-2765(15)00973-9. doi:, 10.1016/j.molcel.2015.12.017. PMID:26778126 doi:http://dx.doi.org/10.1016/j.molcel.2015.12.017