| Structural highlights
Disease
[RAD51_HUMAN] Defects in RAD51 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] Defects in RAD51 are the cause of mirror movements type 2 (MRMV2) [MIM:614508]. A disorder characterized by contralateral involuntary movements that mirror voluntary ones. While mirror movements are occasionally found in young children, persistence beyond the age of 10 is abnormal. Mirror movements occur more commonly in the upper extremities.[2] [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.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] 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.[23] 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.[24] [25] [26] 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.[27]
Function
[RAD51_HUMAN] Participates in a common DNA damage response pathway associated with the activation of homologous recombination and double-strand break repair. Binds to single and double stranded DNA and exhibits DNA-dependent ATPase activity. Underwinds duplex DNA and forms helical nucleoprotein filaments. Plays a role in regulating mitochondrial DNA copy number under conditions of oxidative stress in the presence of RAD51C and XRCC3.[28] [29] [30] [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.[31] [32] [33] [34] [35] [36] [37] [38]
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 breast cancer susceptibility protein BRCA2 controls the function of RAD51, a recombinase enzyme, in pathways for DNA repair by homologous recombination. We report here the structure of a complex between an evolutionarily conserved sequence in BRCA2 (the BRC repeat) and the RecA-homology domain of RAD51. The BRC repeat mimics a motif in RAD51 that serves as an interface for oligomerization between individual RAD51 monomers, thus enabling BRCA2 to control the assembly of the RAD51 nucleoprotein filament, which is essential for strand-pairing reactions during DNA recombination. The RAD51 oligomerization motif is highly conserved among RecA-like recombinases, highlighting a common evolutionary origin for the mechanism of nucleoprotein filament formation, mirrored in the BRC repeat. Cancer-associated mutations that affect the BRC repeat disrupt its predicted interaction with RAD51, yielding structural insight into mechanisms for cancer susceptibility.
Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.,Pellegrini L, Yu DS, Lo T, Anand S, Lee M, Blundell TL, Venkitaraman AR Nature. 2002 Nov 21;420(6913):287-93. Epub 2002 Nov 10. PMID:12442171[39]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kato M, Yano K, Matsuo F, Saito H, Katagiri T, Kurumizaka H, Yoshimoto M, Kasumi F, Akiyama F, Sakamoto G, Nagawa H, Nakamura Y, Miki Y. Identification of Rad51 alteration in patients with bilateral breast cancer. J Hum Genet. 2000;45(3):133-7. PMID:10807537 doi:10.1007/s100380050199
- ↑ Depienne C, Bouteiller D, Meneret A, Billot S, Groppa S, Klebe S, Charbonnier-Beaupel F, Corvol JC, Saraiva JP, Brueggemann N, Bhatia K, Cincotta M, Brochard V, Flamand-Roze C, Carpentier W, Meunier S, Marie Y, Gaussen M, Stevanin G, Wehrle R, Vidailhet M, Klein C, Dusart I, Brice A, Roze E. RAD51 haploinsufficiency causes congenital mirror movements in humans. Am J Hum Genet. 2012 Feb 10;90(2):301-7. doi: 10.1016/j.ajhg.2011.12.002. Epub, 2012 Feb 2. PMID:22305526 doi:10.1016/j.ajhg.2011.12.002
- ↑ Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J, Christ N, Liu X, Jasin M, Couch FJ, Livingston DM. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006 Jun 23;22(6):719-29. PMID:16793542 doi:10.1016/j.molcel.2006.05.022
- ↑ Miki Y, Katagiri T, Kasumi F, Yoshimoto T, Nakamura Y. Mutation analysis in the BRCA2 gene in primary breast cancers. Nat Genet. 1996 Jun;13(2):245-7. PMID:8640237 doi:10.1038/ng0696-245
- ↑ Vehmanen P, Friedman LS, Eerola H, Sarantaus L, Pyrhonen S, Ponder BA, Muhonen T, Nevanlinna H. A low proportion of BRCA2 mutations in Finnish breast cancer families. Am J Hum Genet. 1997 May;60(5):1050-8. PMID:9150152
- ↑ Ganguly T, Dhulipala R, Godmilow L, Ganguly A. High throughput fluorescence-based conformation-sensitive gel electrophoresis (F-CSGE) identifies six unique BRCA2 mutations and an overall low incidence of BRCA2 mutations in high-risk BRCA1-negative breast cancer families. Hum Genet. 1998 May;102(5):549-56. PMID:9654203
- ↑ 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
- ↑ Wagner TM, Hirtenlehner K, Shen P, Moeslinger R, Muhr D, Fleischmann E, Concin H, Doeller W, Haid A, Lang AH, Mayer P, Petru E, Ropp E, Langbauer G, Kubista E, Scheiner O, Underhill P, Mountain J, Stierer M, Zielinski C, Oefner P. Global sequence diversity of BRCA2: analysis of 71 breast cancer families and 95 control individuals of worldwide populations. Hum Mol Genet. 1999 Mar;8(3):413-23. PMID:9971877
- ↑ Sinilnikova OM, Egan KM, Quinn JL, Boutrand L, Lenoir GM, Stoppa-Lyonnet D, Desjardins L, Levy C, Goldgar D, Gragoudas ES. Germline brca2 sequence variants in patients with ocular melanoma. Int J Cancer. 1999 Jul 30;82(3):325-8. PMID:10399947
- ↑ Plaschke J, Commer T, Jacobi C, Schackert HK, Chang-Claude J. BRCA2 germline mutations among early onset breast cancer patients unselected for family history of the disease. J Med Genet. 2000 Sep;37(9):E17. PMID:10978364
- ↑ Kwiatkowska E, Teresiak M, Lamperska KM, Karczewska A, Breborowicz D, Stawicka M, Godlewski D, Krzyzosiak WJ, Mackiewicz A. BRCA2 germline mutations in male breast cancer patients in the Polish population. Hum Mutat. 2001;17(1):73. PMID:11139248 doi:<73::AID-HUMU12>3.0.CO;2-O 10.1002/1098-1004(2001)17:1<73::AID-HUMU12>3.0.CO;2-O
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- ↑ Fackenthal JD, Cartegni L, Krainer AR, Olopade OI. BRCA2 T2722R is a deleterious allele that causes exon skipping. Am J Hum Genet. 2002 Sep;71(3):625-31. Epub 2002 Jul 19. PMID:12145750 doi:S0002-9297(07)60342-5
- ↑ Jakubowska A, Nej K, Huzarski T, Scott RJ, Lubinski J. BRCA2 gene mutations in families with aggregations of breast and stomach cancers. Br J Cancer. 2002 Oct 7;87(8):888-91. PMID:12373604 doi:10.1038/sj.bjc.6600562
- ↑ Zhi X, Szabo C, Chopin S, Suter N, Wang QS, Ostrander EA, Sinilnikova OM, Lenoir GM, Goldgar D, Shi YR. BRCA1 and BRCA2 sequence variants in Chinese breast cancer families. Hum Mutat. 2002 Dec;20(6):474. PMID:12442274 doi:10.1002/humu.9083
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Claes K, Poppe B, Coene I, Paepe AD, Messiaen L. BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. Br J Cancer. 2004 Mar 22;90(6):1244-51. PMID:15026808 doi:10.1038/sj.bjc.6601656
- ↑ Hadjisavvas A, Charalambous E, Adamou A, Neuhausen SL, Christodoulou CG, Kyriacou K. Hereditary breast and ovarian cancer in Cyprus: identification of a founder BRCA2 mutation. Cancer Genet Cytogenet. 2004 Jun;151(2):152-6. PMID:15172753 doi:10.1016/j.cancergencyto.2003.09.020
- ↑ 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
- ↑ Seo JH, Cho DY, Ahn SH, Yoon KS, Kang CS, Cho HM, Lee HS, Choe JJ, Choi CW, Kim BS, Shin SW, Kim YH, Kim JS, Son GS, Lee JB, Koo BH. BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer. Hum Mutat. 2004 Oct;24(4):350. PMID:15365993 doi:10.1002/humu.9275
- ↑ Ozcelik H, Schmocker B, Di Nicola N, Shi XH, Langer B, Moore M, Taylor BR, Narod SA, Darlington G, Andrulis IL, Gallinger S, Redston M. Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet. 1997 May;16(1):17-8. PMID:9140390 doi:10.1038/ng0597-17
- ↑ Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D'Andrea AD. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002 Jul 26;297(5581):606-9. Epub 2002 Jun 13. PMID:12065746 doi:10.1126/science.1073834
- ↑ 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
- ↑ Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet. 2007 Jan;44(1):1-9. Epub 2006 Jul 6. PMID:16825431 doi:jmg.2006.043257
- ↑ Reid S, Renwick A, Seal S, Baskcomb L, Barfoot R, Jayatilake H, Pritchard-Jones K, Stratton MR, Ridolfi-Luthy A, Rahman N. Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. J Med Genet. 2005 Feb;42(2):147-51. PMID:15689453 doi:10.1136/jmg.2004.022673
- ↑ Park JY, Yoo HW, Kim BR, Park R, Choi SY, Kim Y. Identification of a novel human Rad51 variant that promotes DNA strand exchange. Nucleic Acids Res. 2008 Jun;36(10):3226-34. doi: 10.1093/nar/gkn171. Epub 2008, Apr 16. PMID:18417535 doi:10.1093/nar/gkn171
- ↑ Sigurdsson S, Van Komen S, Petukhova G, Sung P. Homologous DNA pairing by human recombination factors Rad51 and Rad54. J Biol Chem. 2002 Nov 8;277(45):42790-4. Epub 2002 Aug 29. PMID:12205100 doi:10.1074/jbc.M208004200
- ↑ Sage JM, Gildemeister OS, Knight KL. Discovery of a novel function for human Rad51: maintenance of the mitochondrial genome. J Biol Chem. 2010 Jun 18;285(25):18984-90. doi: 10.1074/jbc.M109.099846. Epub, 2010 Apr 22. PMID:20413593 doi:10.1074/jbc.M109.099846
- ↑ Hussain S, Wilson JB, Medhurst AL, Hejna J, Witt E, Ananth S, Davies A, Masson JY, Moses R, West SC, de Winter JP, Ashworth A, Jones NJ, Mathew CG. Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways. Hum Mol Genet. 2004 Jun 15;13(12):1241-8. Epub 2004 Apr 28. PMID:15115758 doi:10.1093/hmg/ddh135
- ↑ 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
- ↑ Pellegrini L, Yu DS, Lo T, Anand S, Lee M, Blundell TL, Venkitaraman AR. Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature. 2002 Nov 21;420(6913):287-93. Epub 2002 Nov 10. PMID:12442171 doi:10.1038/nature01230
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