Rad51

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Rad51
Rad51
Crystal structure of a Rad51 filament according to PDB  1SZP

Existing structural data : 1B22 , 1N0W

Properties of human protein
Mass / length primary structure 26.4 - 37.0 kilodaltons / 280 - 340 amino acids (depending on isoform)
Isoforms 4th
Identifier
Gene names RAD51 BRCC5; FANCR; HRAD51; HsRad51; HsT16930; MRMV2; RAD51A; RECA
External IDs
Orthologue
human House mouse
Entrez 5888 19361
Ensemble ENSG00000051180 ENSMUSG00000027323
UniProt Q06609 Q08297
Refseq (mRNA) NM_001164269 NM_011234
Refseq (protein) NP_001157741 NP_035364
Gene locus Chr 15: 40.69 - 40.73 Mb Chr 2: 119.11 - 119.15 Mb
PubMed search 5888 19361

Rad51 is a DNA-binding protein found in eukaryotes and a member of the RAD51 protein family that has a role in DNA repair in double-strand breaks. RAD51 proteins are homologues to the bacterial proteins RecA and to Rad51 from baker's yeast . The protein sequence is very strongly conserved , ie the amino acid sequences of the respective proteins are similar from yeast to humans. In general, in eukaryotes (complex cellular organisms), in addition to Rad51, DMC1 is also found as a homologous protein, whereas in archaea RadA and in bacteriophage T4 finally UvsX .

variants

There are two alternatively spliced variants of the gene , each coding for different proteins. Variants of transcription using alternative poly A signals also exist.

Functions

In humans, RAD51 is a 339 amino acid long protein that plays a major role in the homologous recombination of DNA in double-strand break repair. A DNA strand is exchanged while consuming ATP by inserting a DNA strand into a base-paired homologous DNA sequence. RAD51 looks for homologous areas and helps with DNA attachment.

The family of RecA / Rad51 proteins form a helical nucleoprotein filament on DNA. The structure of this Rad51 filament formation's functional mechanism has not yet been fully elucidated. Studies using fluorescent RAD51 have shown that Rad51 fragments elongate and grow until they are about 2 µm in length. The dissociation of Rad51 from the dsDNA, on the other hand, is slow and incomplete, so that another mechanism could be involved.

pathology

Because the protein interacts with PALB2 and BRCA2 , it may be important in the cell's response to DNA damage. BRCA2 regulates the intracellular position and DNA binding ability of the RAD51. Loss of this control followed by BRCA2 inactivation could be a key event that can lead to genomic instability and tumorigenesis.

The Rad51 gene is located on chromosome 15 in humans and some changes have been linked to an increased risk of breast cancer. The proteins BRCA2 and PALB2 , perhaps involved in breast cancer, control the function of Rad51 during DNA repair through homologous recombination.

Elevated RAD51 expression was discovered in canine breast cancers, suggesting that genomic instability plays an important role in this type of tumor.

family

Seven recA-like genes have been discovered in mammals: Rad51, Rad51L1 / B, Rad51L2 / C, Rad51L3 / D, XRCC2, XRCC3, and DMC1 / Lim15. All proteins, except DMC1, are essential for mammalian development. Rad51 is a member of the RecA-related NTPases .

Interactions

RAD51 interacts with BRE, RAD54B, Ataxia telangiectasia mutated, BRCC3, BARD1, BRCA2, UBE2I, Abl, BRCA1, ATRX, RAD52, DMC1, P53 and the Bloom Syndrome protein.

Web links

Individual evidence

  1. ↑ Haseltine CA, Kowalczykowski SC: An archaeal Rad54 protein remodels DNA and stimulates DNA strand exchange by RadA . In: Nucleic Acids Research . 37, No. 8, May 2009, pp. 2757-2770. doi : 10.1093 / nar / gkp068 . PMID 19282450 . PMC 2677860 (free full text).
  2. ↑ Galkin VE, Wu Y, Zhang XP, Qian X, He Y, Yu X, Heyer WD, Luo Y, Egelman EH: The Rad51 / RadA N-terminal domain activates nucleoprotein filament ATPase activity . In: Structure . 14, No. 6, 2006, pp. 983-92. doi : 10.1016 / j.str.2006.04.001 . PMID 16765891 .
  3. ↑ Hilario J, Amitani I, Baskin RJ, Kowalczykowski SC: Direct imaging of human Rad51 nucleoprotein dynamics on individual DNA molecules . In: Proc. Natl. Acad. Sci. USA . 106, No. 2, January 2009, pp. 361-8. doi : 10.1073 / pnas.0811965106 . PMID 19122145 . PMC 2613362 (free full text).
  4. ↑ a b Buisson R, Dion-Côté AM, et al. : Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. . In: Nature Structural & Molecular Biology . 17, No. 10, 2010, pp. 1247-54. doi : 10.1038 / nsmb.1915 . PMID 20871615 .
  5. ↑ Daniel DC: Highlight: BRCA1 and BRCA2 proteins in breast cancer. . In: Microsc. Res. Tech. . 59, No. 1, 2002, pp. 68-83. doi : 10.1002 / Jemt.10178 . PMID 12242698 .
  6. ↑ a b Luca Pellegrini, David S. Yu, Thomas Lo, Shubha Anand, MiYoung Lee, Tom L. Blundell, Ashok R. Venkitaraman: Insights into DNA recombination from the structure of a RAD51-BRCA2 complex . In: Nature . 420, No. 6913, November 2002, ISSN  0028-0836 , pp. 287-93. doi : 10.1038 / nature01230 . PMID 12442171 .
  7. ↑ Klopfleisch R, by Euler H, Sarli G, Pinho SS, Gärtner F, Gruber AD .: Molecular Carcinogenesis of Canine Mammary Tumors: News From an Old Disease . In: Veterinary Pathology . 228, No. 1, 2010, pp. 98-116. doi : 10.1177 / 0300985810390826 . PMID 21149845 .
  8. ↑ Klopfleisch R, Gruber AD .: Increased expression of BRCA2 and RAD51 in lymph node metastases of canine mammary adenocarcinomas . In: Veterinary Pathology . 46, No. 3, 2009, pp. 416-22. doi : 10.1354 / vp.08-VP-0212-K-FL . PMID 19176491 .
  9. ↑ Klopfleisch R, Schütze M, Gruber AD .: RAD51 protein expression is increased in canine mammary carcinomas . In: Veterinary Pathology . 47, No. 1, 2010, pp. 98-101. doi : 10.1177 / 0300985809353310 . PMID 20080488 .
  10. ↑ Klopfleisch R, Klose P, Gruber AD .: The combined expression pattern of BMP2, LTBP4, and DERL1 discriminates malignant from benign canine mammary tumors . In: Veterinary Pathology. . 47, No. 3, 2010, pp. 446-54 :. doi : 10.1177 / 0300985810363904 . PMID 20375427 .
  11. ↑ Kawabata M, Kawabata T, Nishibori M: Role of recA / RAD51 family proteins in mammals . In: Acta Med Okayama . 59, No. 1, 2005, pp. 1-9. PMID 15902993 .
  12. ↑ a b c d e f Yuanshu Dong, Hakimi Mohamed-Ali, Chen Xiaowei, Kumaraswamy Easwari, Cooch Neil S, Godwin Andrew K, Shiekhattar Ramin: Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair . In: Mol. Cell . 12, No. 5, United States, November 2003, ISSN  1097-2765 , pp. 1087-99. doi : 10.1016 / S1097-2765 (03) 00424-6 . PMID 14636569 .
  13. ^ A b K Tanaka, Hiramoto T, Fukuda T, Miyagawa K: A novel human rad54 homologue, Rad54B, associates with Rad51 . In: J. Biol. Chem. . 275, No. 34, UNITED STATES, August 2000, ISSN  0021-9258 , pp. 26316-21. doi : 10.1074 / jbc.M910306199 . PMID 10851248 .
  14. ↑ a b c G Chen, Yuan SS, Liu W, Xu Y, Trujillo K, Song B, Cong F, Goff SP, Wu Y, Arlinghaus R, Baltimore D, Gasser PJ, Park MS, Sung P, Lee EY: Radiation -induced assembly of Rad51 and Rad52 recombination complex requires ATM and c-Abl . In: J. Biol. Chem. . 274, No. 18, UNITED STATES, April 1999, ISSN  0021-9258 , pp. 12748-52. doi : 10.1074 / jbc.274.18.12748 . PMID 10212258 .
  15. ↑ SK Sharan, Morimatsu M, Albrecht U, Lim DS, Rule E, Dinh C, Sands A, Eichele G, Hasty P, Bradley A: Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2 . In: Nature . 386, No. 6627, ENGLAND, April 1997, ISSN  0028-0836 , pp. 804-10. doi : 10.1038 / 386804a0 . PMID 9126738 .
  16. ↑ Horng-Ru Lin, Ting Nicholas SY, Qin Jun, Lee Wen-Hwa: M phase-specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P / CAF complex . In: J. Biol. Chem. . 278, No. 38, United States, September 2003, ISSN  0021-9258 , pp. 35979-87. doi : 10.1074 / jbc.M210659200 . PMID 12815053 .
  17. ↑ David S Yu, Sonoda Eiichiro, Takeda Shunichi, Huang Christopher LH, Pellegrini Luca, Blundell Tom L, Venkitaraman Ashok R: Dynamic control of Rad51 recombinase by self-association and interaction with BRCA2 . In: Mol. Cell . 12, No. 4, United States, October 2003, ISSN  1097-2765 , pp. 1029-41. doi : 10.1016 / S1097-2765 (03) 00394-0 . PMID 14580352 .
  18. ↑ PL Chen, Chen CF, Chen Y, Xiao J, Sharp ZD, Lee WH: The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment . In: Proc. Natl. Acad. Sci. USA . 95, No. 9, UNITED STATES, April 1998, ISSN  0027-8424 , pp. 5287-92. doi : 10.1073 / pnas.95.9.5287 . PMID 9560268 . PMC 20253 (free full text).
  19. ↑ CJ Sarkisian, Master SR, Huber LJ, Ha SI, Chodosh LA: Analysis of murine Brca2 reveals conservation of protein-protein interactions but differences in nuclear localization signals . In: J. Biol. Chem. . 276, No. 40, United States, October 2001, ISSN  0021-9258 , pp. 37640-8. doi : 10.1074 / jbc.M106281200 . PMID 11477095 .
  20. ^ AK Wong, Pero R, Ormonde PA, Tavtigian SV, Bartel PL: RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2 . In: J. Biol. Chem. . 272, No. 51, UNITED STATES, Dec 1997, ISSN  0021-9258 , pp. 31941-4. doi : 10.1074 / jbc.272.51.31941 . PMID 9405383 .
  21. ^ T Katagiri, Saito H, Shinohara A, Ogawa H, Kamada N, Nakamura Y, Miki Y: Multiple possible sites of BRCA2 interacting with DNA repair protein RAD51 . In: Genes Chromosomes Cancer . 21, No. 3, UNITED STATES, March 1998, ISSN  1045-2257 , pp. 217-22. doi : 10.1002 / (SICI) 1098-2264 (199803) 21: 3 <217 :: AID-GCC5> 3.0.CO; 2-2 . PMID 9523196 .
  22. ↑ Madalena Tarsounas, Davies Adelina A, West Stephen C: RAD51 localization and activation following DNA damage . In: Philos. Trans. R. Soc. Lond., B, Biol. Sci. . 359, No. 1441, England, January 2004, ISSN  0962-8436 , pp. 87-93. doi : 10.1098 / rstb.2003.1368 . PMID 15065660 . PMC 1693300 (free full text).
  23. ^ J Liu, Yuan Y, Huan J, Shen Z: Inhibition of breast and brain cancer cell growth by BCCIPalpha, an evolutionarily conserved nuclear protein that interacts with BRCA2 . In: Oncogene . 20, No. 3, England, January 2001, ISSN  0950-9232 , pp. 336-45. doi : 10.1038 / sj.onc.1204098 . PMID 11313963 .
  24. ↑ a b J Chen, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R: Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells . In: Mol. Cell . 2, No. 3, UNITED STATES, September 1998, ISSN  1097-2765 , pp. 317-28. doi : 10.1016 / S1097-2765 (00) 80276-2 . PMID 9774970 .
  25. ^ LY Marmorstein, Ouchi T, Aaronson SA: The BRCA2 gene product functionally interacts with p53 and RAD51 . In: Proc. Natl. Acad. Sci. USA . 95, No. 23, UNITED STATES, November 1998, ISSN  0027-8424 , pp. 13869-74. doi : 10.1073 / pnas.95.23.13869 . PMID 9811893 . PMC 24938 (free full text).
  26. ↑ OV Kovalenko, Plug AW, Haaf T, Gonda DK, Ashley T, Ward DC, Radding CM, Golub EI: Mammalian ubiquitin-conjugating enzyme Ubc9 interacts with Rad51 recombination protein and localizes in synaptonemal complexes . In: Proc. Natl. Acad. Sci. USA . 93, No. 7, UNITED STATES, April 1996, ISSN  0027-8424 , pp. 2958-63. doi : 10.1073 / pnas.93.7.2958 . PMID 8610150 . PMC 39742 (free full text).
  27. ↑ Z Shen, Pardington-Purtymun PE, Comeaux JC, Moyzis RK, Chen DJ: Associations of UBE2I with RAD52, UBL1, p53, and RAD51 proteins in a yeast two-hybrid system . In: Genomics . 37, No. 2, UNITED STATES, October 1996, ISSN  0888-7543 , pp. 183-6. doi : 10.1006 / geno.1996.0540 . PMID 8921390 .
  28. ^ R Scully, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, Livingston DM: Association of BRCA1 with Rad51 in mitotic and meiotic cells . In: Cell . 88, No. 2, UNITED STATES, January 1997, ISSN  0092-8674 , pp. 265-75. doi : 10.1016 / S0092-8674 (00) 81847-4 . PMID 9008167 .
  29. ↑ Q Wang, Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T, Slupianek A, Skorski T, Fishel R, Greene MI: Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1 . In: Oncogene . 20, No. 34, England, August 2001, ISSN  0950-9232 , pp. 4640-9. doi : 10.1038 / sj.onc.1204625 . PMID 11498787 .
  30. ↑ Stefan Sigurdsson, Van Komen Stephen, Petukhova Galina, Sung Patrick: Homologous DNA pairing by human recombination factors Rad51 and Rad54 . In: J. Biol. Chem. . 277, No. 45, United States, November 2002, ISSN  0021-9258 , pp. 42790-4. doi : 10.1074 / jbc.M208004200 . PMID 12205100 .
  31. ↑ JY Masson, Davies AA, Hajibagheri N, Van Dyck E, Benson FE, Stasiak AZ, Stasiak A, West SC: The meiosis-specific recombinase hDmc1 forms ring structures and interacts with hRad51 . In: EMBO J. . 18, No. 22, ENGLAND, November 1999, ISSN  0261-4189 , pp. 6552-60. doi : 10.1093 / emboj / 18.22.6552 . PMID 10562567 . PMC 1171718 (free full text).
  32. ↑ HW Stürzbecher, Donzelmann B, Henning W, Knippschild U, Buchhop S: p53 is linked directly to homologous recombination processes via RAD51 / RecA protein interaction . In: EMBO J. . 15, No. 8, ENGLAND, April 1996, ISSN  0261-4189 , pp. 1992-2002. PMID 8617246 . PMC 450118 (free full text).
  33. ↑ S Buchhop, Gibson MK, Wang XW, Wagner P, Stürzbecher HW, Harris CC: Interaction of p53 with the human Rad51 protein . In: Nucleic Acids Res . 25, No. 19, ENGLAND, October 1997, ISSN  0305-1048 , pp. 3868-74. doi : 10.1093 / nar / 25.19.3868 . PMID 9380510 . PMC 146972 (free full text).
  34. ↑ L Wu, Davies SL, Levitt NC, Hickson ID: Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51 . In: J. Biol. Chem. . 276, No. 22, United States, June 2001, ISSN  0021-9258 , pp. 19375-81. doi : 10.1074 / jbc.M009471200 . PMID 11278509 .