RAD51
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Un filamento de Rad51 baseado en PDB 1SZP | |
Recombinase RAD51
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Identificadores | |
Símbolo | RAD51 |
Símbolos alt. | BRCC5; HRAD51; HsRad51; HsT16930; MRMV2; RAD51A; RECA |
Entrez | 5888 |
OMIM | |
RefSeq | NP_001157741 |
UniProt | Q06609 |
Outros datos | |
Locus | Cr. 15 :(40.99 – 41.02 Mb) |
RAD51 é un xene eucariota que codifica unha proteína que pertence á familia da proteína RAD51, que axuda á reparación de roturas de dobre febra no ADN. Os membros da familia de RAD51 son homólogos da proteína bacteriana RecA e da Rad51 do lévedo Saccharomyces cerevisiae. A proteína está moi conservada na maioría dos eucariotas, desde os lévedos aos humanos.
Variantes
[editar | editar a fonte]Hai dúas variantes de transcrición orixinadas por splicing alternativo desta proteína. Existen variantes de transcrición que utilizan sinais poliA alternativos.
Función
[editar | editar a fonte]Nos humanos, RAD51 é unha proteína de 339 aminoácidos que xoga un importante papel na recombinación homóloga do ADN durante a reparación de roturas de dobre febra. Neste proceso, ten lugar un intercambio de febras de ADN dependente de ATP no cal unha febra molde invade febras apareadas de moléculas de ADN homólogas. A RAD51 intervén nas etapas de busca de homoloxía e de apareamento deste proceso.
A diferenza doutras proteínas implicadas no metabolismo do ADN, a familia RecA/Rad51 forma un filamento de nucleoproteína helicoidal no ADN.[1]
Esta proteína pode interaccionar coas proteínas de unión ao ADN monocatenario RPA, BRCA2, PALB2[2] e RAD52.
Como se dixo, esta proteína forma filamentos. A base estrutural para a formación de filamentos de Rad51 e o seu mecanismo funcional aínda non está aclarado. Porén, estudos recentes feitos utilizando proteínas Rad51 etiquetadas fluorescentemente[3] indican que os fragmentos de Rad51 se alongan por eventos de nucleación múltiple seguidos de crecemento, e o fragmento total está terminado cando atinxe uns 2 μm de lonxitude. Porén, a disociación de Rad51 do ADN bicatenario é lenta e incompleta, o que suxire que hai un mecanismo adicional que realiza isto.
Patoloxía
[editar | editar a fonte]Esta proteína interacciona con PALB2[2] e BRCA2, o que pode ser importante para a resposta celular aos danos no ADN. BRCA2 regula tanto a localización intracelular coma a capacidade de unión ao ADN desta proteína. A perda destes controis despois da inactivación de BRCA2 pode ser un evento clave que orixine unha inestabilidade xenómica e xénese de tumores.[4]
O xene Rad51 está localizado no cromosoma 15 humano e asociáronse varias alteracións neste xene cun incremento do risco de desenvolver cancro de mama. A proteína de susceptibilidade ao cancro de mama BRCA2 e PALB2 controlan o funcionamento de Rad51 na vía de reparación do ADN por recombinación homóloga.[2][5] Observouse un incremento dos niveis de expresión de RAD51 no carcinoma mamario canino metastático, o que indica que a inestabilidade xenómica xoga un importantes papel na carcinoxénese deste tipo de tumores.[6][7][8][9]
Familia
[editar | editar a fonte]Nos mamíferos identificáronse sete xenes de tipo recA, que son: Rad51, Rad51L1/B, Rad51L2/C, Rad51L3/D, XRCC2, XRCC3, e DMC1/Lim15.[10] Todas estas proteínas, coa excepción da DNC1 específica da meiose, son esenciais para o desenvolvemento dos mamíferos. Rad51 é un membro das NTPases de tipo RecA.
Interaccións
[editar | editar a fonte]A RAD51 presenta interaccións con BRE,[11] RAD54,[12] RAD54B,[13] ataxia telanxiectasia mutada,[14] BRCC3,[11] BARD1,[11] BRCA2,[11][15][16][17][18][19][20][21][5][22][23][24][25] UBE2I,[26][27] xene Abl,[14] BRCA1,[11][24][28][29] RAD52,[14] DMC1,[30] P53[11][31][32] e coa proteína da síndrome de Bloom.[33]
Notas
[editar | editar a fonte]- ↑ Galkin VE, Wu Y, Zhang XP, Qian X, He Y, Yu X, Heyer WD, Luo Y, Egelman EH (2006). "The Rad51/RadA N-terminal domain activates nucleoprotein filament ATPase activity". Structure 14 (6): 983–92. PMID 16765891. doi:10.1016/j.str.2006.04.001.
- ↑ 2,0 2,1 2,2 Buisson R, Dion-Côté A.M; et al. (2010). "Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination.". Nature Structural & molecular biology 17 (10): 1247–54. PMID 20871615. doi:10.1038/nsmb.1915.
- ↑ Hilario J, Amitani I, Baskin RJ, Kowalczykowski SC (January 2009). "Direct imaging of human Rad51 nucleoprotein dynamics on individual DNA molecules". Proc. Natl. Acad. Sci. U.S.A. 106 (2): 361–8. PMC 2613362. PMID 19122145. doi:10.1073/pnas.0811965106.
- ↑ Daniel DC (2002). "Highlight: BRCA1 and BRCA2 proteins in breast cancer.". Microsc. Res. Tech. 59 (1): 68–83. PMID 12242698. doi:10.1002/jemt.10178.
- ↑ 5,0 5,1 Pellegrini, Luca; Yu David S; Lo Thomas; Anand Shubha; Lee MiYoung; Blundell Tom L; Venkitaraman Ashok R (November 2002). "Insights into DNA recombination from the structure of a RAD51-BRCA2 complex". Nature (England) 420 (6913): 287–93. ISSN 0028-0836. PMID 12442171. doi:10.1038/nature01230.
- ↑ Klopfleisch R, von Euler H, Sarli G, Pinho SS, Gärtner F, Gruber AD. (2010). "Molecular Carcinogenesis of Canine Mammary Tumors: News From an Old Disease". Veterinary Pathology 228 (1): 98–116. PMID 21149845. doi:10.1177/0300985810390826.
- ↑ Klopfleisch R, Gruber AD. (2009). "Increased expression of BRCA2 and RAD51 in lymph node metastases of canine mammary adenocarcinomas". Veterinary Pathology 46 (3): 416–22. PMID 19176491. doi:10.1354/vp.08-VP-0212-K-FL.
- ↑ Klopfleisch R, Schütze M, Gruber AD. (2010). "RAD51 protein expression is increased in canine mammary carcinomas". Veterinary Pathology 47 (1): 98–101. PMID 20080488. doi:10.1177/0300985809353310.
- ↑ Klopfleisch R, Klose P, Gruber AD. (2010). "The combined expression pattern of BMP2, LTBP4, and DERL1 discriminates malignant from benign canine mammary tumors". Veterinary Pathology. 47 (3): 446–54:. PMID 20375427. doi:10.1177/0300985810363904.
- ↑ Kawabata M, Kawabata T, Nishibori M (2005). "Role of recA/RAD51 family proteins in mammals". Acta Med Okayama 59 (1): 1–9. PMID 15902993.
- ↑ 11,0 11,1 11,2 11,3 11,4 11,5 Dong, Yuanshu; Hakimi Mohamed-Ali; Chen Xiaowei; Kumaraswamy Easwari; Cooch Neil S; Godwin Andrew K; Shiekhattar Ramin (November 2003). "Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair". Mol. Cell (United States) 12 (5): 1087–99. ISSN 1097-2765. PMID 14636569. doi:10.1016/S1097-2765(03)00424-6.
- ↑ Sigurdsson, Stefan; Van Komen Stephen; Petukhova Galina; Sung Patrick (November 2002). "Homologous DNA pairing by human recombination factors Rad51 and Rad54". J. Biol. Chem. (United States) 277 (45): 42790–4. ISSN 0021-9258. PMID 12205100. doi:10.1074/jbc.M208004200.
- ↑ Tanaka, K; Hiramoto T; Fukuda T; Miyagawa K (August 2000). "A novel human rad54 homologue, Rad54B, associates with Rad51". J. Biol. Chem. (UNITED STATES) 275 (34): 26316–21. ISSN 0021-9258. PMID 10851248. doi:10.1074/jbc.M910306199.
- ↑ 14,0 14,1 14,2 Chen, G; Yuan S S, Liu W, Xu Y, Trujillo K, Song B, Cong F, Goff S P, Wu Y, Arlinghaus R, Baltimore D, Gasser P J, Park M S, Sung P, Lee E Y (April 1999). "Radiation-induced assembly of Rad51 and Rad52 recombination complex requires ATM and c-Abl". J. Biol. Chem. (UNITED STATES) 274 (18): 12748–52. ISSN 0021-9258. PMID 10212258. doi:10.1074/jbc.274.18.12748.
- ↑ Sharan, S K; Morimatsu M; Albrecht U; Lim D S; Regel E; Dinh C; Sands A; Eichele G; Hasty P; Bradley A (April 1997). "Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2". Nature (ENGLAND) 386 (6627): 804–10. ISSN 0028-0836. PMID 9126738. doi:10.1038/386804a0.
- ↑ Lin, Horng-Ru; Ting Nicholas S Y; Qin Jun; Lee Wen-Hwa (September 2003). "M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex". J. Biol. Chem. (United States) 278 (38): 35979–87. ISSN 0021-9258. PMID 12815053. doi:10.1074/jbc.M210659200.
- ↑ Yu, David S; Sonoda Eiichiro; Takeda Shunichi; Huang Christopher L H; Pellegrini Luca; Blundell Tom L; Venkitaraman Ashok R (October 2003). "Dynamic control of Rad51 recombinase by self-association and interaction with BRCA2". Mol. Cell (United States) 12 (4): 1029–41. ISSN 1097-2765. PMID 14580352. doi:10.1016/S1097-2765(03)00394-0.
- ↑ Chen, P L; Chen C F; Chen Y; Xiao J; Sharp Z D; Lee W H (April 1998). "The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 95 (9): 5287–92. ISSN 0027-8424. PMC 20253. PMID 9560268. doi:10.1073/pnas.95.9.5287.
- ↑ Sarkisian, C J; Master S R; Huber L J; Ha S I; Chodosh L A (October 2001). "Analysis of murine Brca2 reveals conservation of protein-protein interactions but differences in nuclear localization signals". J. Biol. Chem. (United States) 276 (40): 37640–8. ISSN 0021-9258. PMID 11477095. doi:10.1074/jbc.M106281200.
- ↑ Wong, A K; Pero R; Ormonde P A; Tavtigian S V; Bartel P L (Dec 1997). "RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2". J. Biol. Chem. (UNITED STATES) 272 (51): 31941–4. ISSN 0021-9258. PMID 9405383. doi:10.1074/jbc.272.51.31941.
- ↑ Katagiri, T; Saito H; Shinohara A; Ogawa H; Kamada N; Nakamura Y; Miki Y (March 1998). "Multiple possible sites of BRCA2 interacting with DNA repair protein RAD51". Genes Chromosomes Cancer (UNITED STATES) 21 (3): 217–22. ISSN 1045-2257. PMID 9523196. doi:10.1002/(SICI)1098-2264(199803)21:3<217::AID-GCC5>3.0.CO;2-2.
- ↑ Tarsounas, Madalena; Davies Adelina A; West Stephen C (January 2004). "RAD51 localization and activation following DNA damage". Philos. Trans. R. Soc. Lond., B, Biol. Sci. (England) 359 (1441): 87–93. ISSN 0962-8436. PMC 1693300. PMID 15065660. doi:10.1098/rstb.2003.1368.
- ↑ Liu, J; Yuan Y; Huan J; Shen Z (January 2001). "Inhibition of breast and brain cancer cell growth by BCCIPalpha, an evolutionarily conserved nuclear protein that interacts with BRCA2". Oncogene (England) 20 (3): 336–45. ISSN 0950-9232. PMID 11313963. doi:10.1038/sj.onc.1204098.
- ↑ 24,0 24,1 Chen, J; Silver D P, Walpita D, Cantor S B, Gazdar A F, Tomlinson G, Couch F J, Weber B L, Ashley T, Livingston D M, Scully R (September 1998). "Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells". Mol. Cell (UNITED STATES) 2 (3): 317–28. ISSN 1097-2765. PMID 9774970. doi:10.1016/S1097-2765(00)80276-2.
- ↑ Marmorstein, L Y; Ouchi T; Aaronson S A (November 1998). "The BRCA2 gene product functionally interacts with p53 and RAD51". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 95 (23): 13869–74. ISSN 0027-8424. PMC 24938. PMID 9811893. doi:10.1073/pnas.95.23.13869.
- ↑ Kovalenko, O V; Plug A W; Haaf T; Gonda D K; Ashley T; Ward D C; Radding C M; Golub E I (April 1996). "Mammalian ubiquitin-conjugating enzyme Ubc9 interacts with Rad51 recombination protein and localizes in synaptonemal complexes". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 93 (7): 2958–63. ISSN 0027-8424. PMC 39742. PMID 8610150. doi:10.1073/pnas.93.7.2958.
- ↑ Shen, Z; Pardington-Purtymun P E; Comeaux J C; Moyzis R K; Chen D J (October 1996). "Associations of UBE2I with RAD52, UBL1, p53, and RAD51 proteins in a yeast two-hybrid system". Genomics (UNITED STATES) 37 (2): 183–6. ISSN 0888-7543. PMID 8921390. doi:10.1006/geno.1996.0540.
- ↑ Scully, R; Chen J; Plug A; Xiao Y; Weaver D; Feunteun J; Ashley T; Livingston D M (January 1997). "Association of BRCA1 with Rad51 in mitotic and meiotic cells". Cell (UNITED STATES) 88 (2): 265–75. ISSN 0092-8674. PMID 9008167. doi:10.1016/S0092-8674(00)81847-4.
- ↑ Wang, Q; Zhang H; Guerrette S; Chen J; Mazurek A; Wilson T; Slupianek A; Skorski T; Fishel R; Greene M I (August 2001). "Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1". Oncogene (England) 20 (34): 4640–9. ISSN 0950-9232. PMID 11498787. doi:10.1038/sj.onc.1204625.
- ↑ Masson, J Y; Davies A A; Hajibagheri N; Van Dyck E; Benson F E; Stasiak A Z; Stasiak A; West S C (November 1999). "The meiosis-specific recombinase hDmc1 forms ring structures and interacts with hRad51". EMBO J. (ENGLAND) 18 (22): 6552–60. ISSN 0261-4189. PMC 1171718. PMID 10562567. doi:10.1093/emboj/18.22.6552.
- ↑ Stürzbecher, H W; Donzelmann B; Henning W; Knippschild U; Buchhop S (April 1996). "p53 is linked directly to homologous recombination processes via RAD51/RecA protein interaction". EMBO J. (ENGLAND) 15 (8): 1992–2002. ISSN 0261-4189. PMC 450118. PMID 8617246.
- ↑ Buchhop, S; Gibson M K; Wang X W; Wagner P; Stürzbecher H W; Harris C C (October 1997). "Interaction of p53 with the human Rad51 protein". Nucleic Acids Res. (ENGLAND) 25 (19): 3868–74. ISSN 0305-1048. PMC 146972. PMID 9380510. doi:10.1093/nar/25.19.3868.
- ↑ Wu, L; Davies S L; Levitt N C; Hickson I D (June 2001). "Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51". J. Biol. Chem. (United States) 276 (22): 19375–81. ISSN 0021-9258. PMID 11278509. doi:10.1074/jbc.M009471200.
Véxase tamén
[editar | editar a fonte]Outros artigos
[editar | editar a fonte]Ligazóns externas
[editar | editar a fonte]- RAD51 Protein Medical Subject Headings (MeSH) na Biblioteca Nacional de Medicina dos EUA.