BRCA1
Component of E3 ubiquitin ligase involved in DNA repair. Thought to stabilize replication forks on DNA damage (1) .
Nb there is a huge literature on this protein and we have not tried to cover all of it just those most relevant for replication.
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BRCA1 |
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Synonyms |
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Molecular weight |
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Biochemical properties |
•DNA binding (2) •E3 Ub ligase activity (stimulated by bard) I ring domain (3)
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Motifs |
•Ring finger (involved ub) •BRCT domains (2)
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Interactions |
Xl •BARD (usually as heterodimer) (4)
Mammals •Ctip (phosphorylation dependent) causes its ub but not degradation (5) •p53 (6) BRCA /bard complex needed for phosphorylation p53 after ir and uv (7) , also needed p53 ub as BRCC complex. Synergistic in tumour development with p53 (8) •Bach1 (helicase) (9) (10) •FancA (11) •FancD2 (12) •rnapolII (13) binds hyperphosphorylated (14) •Swi/snf (15) •Atm (16) (17) •Rad51 (18) •Rb rbap46 /48 hdac1/2 (19) •cabl disrupted in atm dependent way on ionising radiation (20) •nmi/cmv (21) •topoII in S (22) •ws (23) •mdc1 (involved in brca localisation on DNA damage (24) ) •Abraxas ( brct repeats) (25) , (26) •rap80 ( ub binding protein) via abraxas (needed for brca1 accumulation on damaged DNA) (25-28) • rnf8( fha/ring protein) involved in rap80 pathway (29) (30) (31) (32) •Ccdc98 (needed for formation of brca foci after ionising radiation) (28, 33) •Pp1 binding motif ( mutation lethal on damage) (34) • SUMO (represses transcriptional activity) (35)
Complexes reported •4 complexes reported:RNA pol2/ rad50/mre11/nbs plus 2 more (36) , inhibits exo of mrn complex (2) •brcc complex is BRCA1 /BRCA2/rad51 (37) •basc (2mDa) 15 subunits including blm and atm, mre11,rad50,nbs,msh2.msh6 mlh, pms rfc. (38)
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Modifications |
•Phosphorylated g1/s (cdk) •Phosphorylated DNA damage (39) (16) - via atm (40) (41) . Via atr in hu blocked cells •closest homologue is Ub at sites DNA damage in c elegans (42)
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Structure |
brca/bard heterodimer (43) |
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Cellular location and expression |
•Relocates on DNA damage to sites of replication (44) needed for rad51 foci (45) and to recruit atm to sites with nbs1 (46) (activation atm on ionising radiation also requires baat (47) ) •needs h2ax for its localisation (48) , (49) . •Associated inactive x in late s (50) •levels down on m/g1 (51) • in normal S phase nuclei localises interphase centromeres and replicating pericentric heterochromatin (52)
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Other comments |
•Only in vertebrates •Often mutated in familial breast and ovarian cancer syndrome. •Heterozygous Brca1 mice show premature aging (53) •homozygous embryonic lethal – some interaction p53 (54) •Mutants in mouse cells have abnormal g2/m (abnormal chromosomes /multiple centrisomes and abnormal segregation) (55) • several splice variants some found more in quiescent than proliferating cells (56) • Needed to activate chk1 kinase (57) , (this also needs claspin (46) ) • role in controlling plk after DNA damage (58) • positive and negative effects on transcription. eg (59) (60) (61) • effects on decondensation (60) • If tether the transcriptional activation domain brca1 to DNA , alters local chromatin structure and stimulates replication (62)
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Revised by |
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Last edited |
15 April 08 |
1. Farmer,H., McCabe,N., Lord,C.J., Tutt,A.N., Johnson,D.A., Richardson,T.B., Santarosa,M., Dillon,K.J., Hickson,I., Knights,C., Martin,N.M., Jackson,S.P., Smith,G.C. and Ashworth,A. (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917-921.
2. Paull,T.T., Cortez,D., Bowers,B., Elledge,S.J. and Gellert,M. (2001) Direct DNA binding by Brca1. Proc Natl Acad Sci U S A 98, 6086-6091.
3. Wu-Baer,F., Lagrazon,K., Yuan,W. and Baer,R. (2003) The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin. J Biol Chem 278, 34743-34746.
4. Joukov,V., Chen,J., Fox,E.A., Green,J.B. and Livingston,D.M. (2001) Functional communication between endogenous BRCA1 and its partner, BARD1, during Xenopus laevis development. Proc Natl Acad Sci U S A 98, 12078-12083.
5. Yu,X., Fu,S., Lai,M., Baer,R. and Chen,J. (2006) BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev 20, 1721-1726.
6. Xu,X., Qiao,W., Linke,S.P., Cao,L., Li,W.M., Furth,P.A., Harris,C.C. and Deng,C.X. (2001) Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat Genet 28, 266-271.
7. Fabbro,M., Savage,K., Hobson,K., Deans,A.J., Powell,S.N., McArthur,G.A. and Khanna,K.K. (2004) BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage. J Biol Chem 279, 31251-31258.
8. Jonkers,J., Meuwissen,R., van der Gulden,H., Peterse,H., van der Valk,M. and Berns,A. (2001) Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet 29, 418-425.
9. Cantor,S.B., Bell,D.W., Ganesan,S., Kass,E.M., Drapkin,R., Grossman,S., Wahrer,D.C., Sgroi,D.C., Lane,W.S., Haber,D.A. and Livingston,D.M. (2001) BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105, 149-160.
10. Kumaraswamy,E. and Shiekhattar,R. (2007) Activation of BRCA1/BRCA2-associated helicase BACH1 is required for timely progression through S phase. Mol Cell Biol 27, 6733-6741.
11. Folias,A., Matkovic,M., Bruun,D., Reid,S., Hejna,J., Grompe,M., D'Andrea,A. and Moses,R. (2002) BRCA1 interacts directly with the Fanconi anemia protein FANCA. Hum Mol Genet 11, 2591-2597.
12. Garcia-Higuera,I., Taniguchi,T., Ganesan,S., Meyn,M.S., Timmers,C., Hejna,J., Grompe,M. and D'Andrea,A.D. (2001) Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell 7, 249-262.
13. Scully,R., Anderson,S.F., Chao,D.M., Wei,W., Ye,L., Young,R.A., Livingston,D.M. and Parvin,J.D. (1997) BRCA1 is a component of the RNA polymerase II holoenzyme. Proc Natl Acad Sci U S A 94, 5605-5610.
14. Krum,S.A., Miranda,G.A., Lin,C. and Lane,T.F. (2003) BRCA1 associates with processive RNA polymerase II. J Biol Chem 278, 52012-52020.
15. Bochar,D.A., Wang,L., Beniya,H., Kinev,A., Xue,Y., Lane,W.S., Wang,W., Kashanchi,F. and Shiekhattar,R. (2000) BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell 102, 257-265.
16. Lee,J.S., Collins,K.M., Brown,A.L., Lee,C.H. and Chung,J.H. (2000) hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404, 201-204.
17. Foray,N., Marot,D., Gabriel,A., Randrianarison,V., Carr,A.M., Perricaudet,M., Ashworth,A. and Jeggo,P. (2003) A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. EMBO J 22, 2860-2871.
18. Moynahan,M.E., Chiu,J.W., Koller,B.H. and Jasin,M. (1999) Brca1 controls homology-directed DNA repair. Mol Cell 4, 511-518.
19. Yarden,R.I. and Brody,L.C. (1999) BRCA1 interacts with components of the histone deacetylase complex. Proc Natl Acad Sci U S A 96, 4983-4988.
20. Foray,N., Marot,D., Randrianarison,V., Venezia,N.D., Picard,D., Perricaudet,M., Favaudon,V. and Jeggo,P. (2002) Constitutive association of BRCA1 and c-Abl and its ATM-dependent disruption after irradiation. Mol Cell Biol 22, 4020-4032.
21. Li,H., Lee,T.H. and Avraham,H. (2002) A novel tricomplex of BRCA1, Nmi, and c-Myc inhibits c-Myc-induced human telomerase reverse transcriptase gene (hTERT) promoter activity in breast cancer. J Biol Chem 277, 20965-20973.
22. Lou,Z., Minter-Dykhouse,K. and Chen,J. (2005) BRCA1 participates in DNA decatenation. Nat Struct Mol Biol 12, 589-593.
23. Chang,T.W., Wang,S.M., Guo,Y.L., Tsai,P.C., Huang,C.J. and Huang,W. (2006) Glutathione S-transferase polymorphisms associated with risk of breast cancer in southern Taiwan. Breast 15, 754-761.
24. Lou,Z., Chini,C.C., Minter-Dykhouse,K. and Chen,J. (2003) Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and phosphorylation in DNA damage checkpoint control. J Biol Chem 278, 13599-13602.
25. Wang,B., Matsuoka,S., Ballif,B.A., Zhang,D., Smogorzewska,A., Gygi,S.P. and Elledge,S.J. (2007) Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316, 1194-1198.
26. Kim,H., Chen,J. and Yu,X. (2007) Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316, 1202-1205.
27. Sobhian,B., Shao,G., Lilli,D.R., Culhane,A.C., Moreau,L.A., Xia,B., Livingston,D.M. and Greenberg,R.A. (2007) RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316, 1198-1202.
28. Liu,Z., Wu,J. and Yu,X. (2007) CCDC98 targets BRCA1 to DNA damage sites. Nat Struct Mol Biol 14, 716-720.
29. Huen,M.S., Grant,R., Manke,I., Minn,K., Yu,X., Yaffe,M.B. and Chen,J. (2007) RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell 131, 901-914.
30. Kolas,N.K., Chapman,J.R., Nakada,S., Ylanko,J., Chahwan,R., Sweeney,F.D., Panier,S., Mendez,M., Wildenhain,J., Thomson,T.M., Pelletier,L., Jackson,S.P. and Durocher,D. (2007) Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science 318, 1637-1640.
31. Yang,X.H. and Zou,L. (2007) Launching a ubiquitination cascade at DNA breaks. Proc Natl Acad Sci U S A 104, 20645-20646.
32. Bennett,E.J. and Harper,J.W. (2008) DNA damage: ubiquitin marks the spot. Nat Struct Mol Biol 15, 20-22.
33. Kim,H., Huang,J. and Chen,J. (2007) CCDC98 is a BRCA1-BRCT domain-binding protein involved in the DNA damage response. Nat Struct Mol Biol 14, 710-715.
34. Hsu,L.C. (2007) Identification and functional characterization of a PP1-binding site in BRCA1. Biochem Biophys Res Commun 360, 507-512.
35. Park,M.A., Seok,Y.J., Jeong,G. and Lee,J.S. (2008) SUMO1 negatively regulates BRCA1-mediated transcription, via modulation of promoter occupancy. Nucleic Acids Res 36, 263-283.
36. Chiba,N. and Parvin,J.D. (2001) Redistribution of BRCA1 among four different protein complexes following replication blockage. J Biol Chem 276, 38549-38554.
37. Dong,Y., Hakimi,M.A., Chen,X., Kumaraswamy,E., Cooch,N.S., Godwin,A.K. and Shiekhattar,R. (2003) Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol Cell 12, 1087-1099.
38. Wang,Y., Cortez,D., Yazdi,P., Neff,N., Elledge,S.J. and Qin,J. (2000) BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 14, 927-939.
39. Cortez,D., Wang,Y., Qin,J. and Elledge,S.J. (1999) Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286, 1162-1166.
40. Tibbetts,R.S., Cortez,D., Brumbaugh,K.M., Scully,R., Livingston,D., Elledge,S.J. and Abraham,R.T. (2000) Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes Dev 14, 2989-3002.
41. Gatei,M., Zhou,B.B., Hobson,K., Scott,S., Young,D. and Khanna,K.K. (2001) Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specific antibodies. J Biol Chem 276, 17276-17280.
42. Polanowska,J., Martin,J.S., Garcia-Muse,T., Petalcorin,M.I. and Boulton,S.J. (2006) A conserved pathway to activate BRCA1-dependent ubiquitylation at DNA damage sites. EMBO J 25, 2178-2188.
43. Brzovic,P.S., Rajagopal,P., Hoyt,D.W., King,M.C. and Klevit,R.E. (2001) Structure of a BRCA1-BARD1 heterodimeric RING-RING complex. Nat Struct Biol 8, 833-837.
44. Scully,R., Chen,J., Ochs,R.L., Keegan,K., Hoekstra,M., Feunteun,J. and Livingston,D.M. (1997) Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90, 425-435.
45. Bhattacharyya,A., Ear,U.S., Koller,B.H., Weichselbaum,R.R. and Bishop,D.K. (2000) The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J Biol Chem 275, 23899-23903.
46. Lin,S.Y., Li,K., Stewart,G.S. and Elledge,S.J. (2004) Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation. Proc Natl Acad Sci U S A 101, 6484-6489.
47. Aglipay,J.A., Martin,S.A., Tawara,H., Lee,S.W. and Ouchi,T. (2006) ATM activation by ionizing radiation requires BRCA1-associated BAAT1. J Biol Chem 281, 9710-9718.
48. Bassing,C.H., Chua,K.F., Sekiguchi,J., Suh,H., Whitlow,S.R., Fleming,J.C., Monroe,B.C., Ciccone,D.N., Yan,C., Vlasakova,K., Livingston,D.M., Ferguson,D.O., Scully,R. and Alt,F.W. (2002) Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX. Proc Natl Acad Sci U S A 99, 8173-8178.
49. Celeste,A., Petersen,S., Romanienko,P.J., Fernandez-Capetillo,O., Chen,H.T., Sedelnikova,O.A., Reina-San-Martin,B., Coppola,V., Meffre,E., Difilippantonio,M.J., Redon,C., Pilch,D.R., Olaru,A., Eckhaus,M., Camerini-Otero,R.D., Tessarollo,L., Livak,F., Manova,K., Bonner,W.M., Nussenzweig,M.C. and Nussenzweig,A. (2002) Genomic instability in mice lacking histone H2AX. Science296, 922-927.
50. Chadwick,B.P. and Lane,T.F. (2005) BRCA1 associates with the inactive X chromosome in late S-phase, coupled with transient H2AX phosphorylation. Chromosoma 114, 432-439.
51. Choudhury,A.D., Xu,H. and Baer,R. (2004) Ubiquitination and proteasomal degradation of the BRCA1 tumor suppressor is regulated during cell cycle progression. J Biol Chem 279, 33909-33918.
52. Pageau,G.J. and Lawrence,J.B. (2006) BRCA1 foci in normal S-phase nuclei are linked to interphase centromeres and replication of pericentric heterochromatin. J Cell Biol 175, 693-701.
53. Lou,Z. and Chen,J. (2006) Cellular senescence and DNA repair. Exp Cell Res 312, 2641-2646.
54. Cao,L., Kim,S., Xiao,C., Wang,R.H., Coumoul,X., Wang,X., Li,W.M., Xu,X.L., De Soto,J.A., Takai,H., Mai,S., Elledge,S.J., Motoyama,N. and Deng,C.X. (2006) ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency. EMBO J 25, 2167-2177.
55. Xu,X., Weaver,Z., Linke,S.P., Li,C., Gotay,J., Wang,X.W., Harris,C.C., Ried,T. and Deng,C.X. (1999) Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell 3, 389-395.
56. Ashworth,A. (2004) Refocusing on BRCA1. Nat Cell Biol 6, 916-917.
57. Yarden,R.I., Pardo-Reoyo,S., Sgagias,M., Cowan,K.H. and Brody,L.C. (2002) BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nat Genet 30, 285-289.
58. Ree,A.H., Bratland,A., Nome,R.V., Stokke,T. and Fodstad,O. (2003) Repression of mRNA for the PLK cell cycle gene after DNA damage requires BRCA1. Oncogene 22, 8952-8955.
59. Aprelikova,O., Pace,A.J., Fang,B., Koller,B.H. and Liu,E.T. (2001) BRCA1 is a selective co-activator of 14-3-3 sigma gene transcription in mouse embryonic stem cells. J Biol Chem 276, 25647-25650.
60. Ye,Q., Hu,Y.F., Zhong,H., Nye,A.C., Belmont,A.S. and Li,R. (2001) BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations. J Cell Biol 155, 911-921.
61. Zheng,L., Annab,L.A., Afshari,C.A., Lee,W.H. and Boyer,T.G. (2001) BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor. Proc Natl Acad Sci U S A 98, 9587-9592.
62. Hu,Y.F., Hao,Z.L. and Li,R. (1999) Chromatin remodeling and activation of chromosomal DNA replication by an acidic transcriptional activation domain from BRCA1. Genes Dev 13, 637-642.