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Molecular views of recombination proteins and their control

Nature Reviews Molecular Cell Biology volume 4, pages 435–445 (2003)Cite this article

Key Points

  • The efficient repair of double-stranded DNA breaks (DSBs) is essential for genome integrity and cell survival.

  • Homologous recombination is one pathway that is used to repair DSBs, particularly in replicating cells, in which it is involved in avoiding the formation of tumours.

  • Many of the enzymes that are involved in homologous recombination have been isolated by biochemical and genetic methods. One of these, RAD51, catalyses homologous pairing and strand exchange in many species, from yeast to humans.

  • The specificity of RAD51 is enhanced by another key recombination protein that is known as RAD52, and much work has been done on the molecular structure of this protein.

  • The tumour-suppressor proteins BRCA1 and BRCA2 colocalize with RAD51 in DNA-damage-induced nulear foci, and BRCA2 has been shown to interact directly with RAD51.

  • The exact roles of BRCA1, BRCA2 and other proteins — such as BACH1 — in recombinational repair are not yet clear, but the recombination field is moving rapidly and we should not need to wait long for the answers.

Abstract

The efficient repair of double-strand breaks in DNA is critical for the maintenance of genome stability and cell survival. Homologous recombination provides an efficient and faithful pathway of repair, especially in replicating cells, in which it plays a major role in tumour avoidance. Many of the enzymes that are involved in recombination have been isolated, and the details of this pathway are now being unravelled at the molecular level.

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Figure 1: Electron-microscopic visualization of nucleoprotein filaments.
Figure 2: Scheme for the repair of a double-strand break by homologous recombination.
Figure 3: Structure of the 11-subunit RAD521–209 ring.
Figure 4: Localization of RAD51 and RAD52 to nuclear foci.
Figure 5: Functional domains of BRCA1 and BRCA2.
Figure 6: The molecular basis by which BRCA2 controls RAD51.
Figure 7: Interactions between the FA and BRCA proteins.

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References

  1. Cox, M. M. Recombinational DNA repair of damaged replication forks in Escherichia coli: questions. Annu. Rev. Genet. 35, 53–82 (2001).

    CAS  PubMed  Google Scholar 

  2. Ogawa, T., Yu, X., Shinohara, A. & Egelman, E. H. Similarity of the yeast Rad51 filament to the bacterial RecA filament. Science 259, 1896–1899 (1993). The similarity between E. coli RecA and yeast Rad51 was seen by electron microscopy and indicated that the nucleoprotein filament structure that is important for recombination in bacteria has been conserved throughout evolution.

    CAS  PubMed  Google Scholar 

  3. Benson, F. E., Stasiak, A. & West, S. C. Purification and characterisation of the human RAD51 protein, an analogue of E. coli RecA. EMBO J. 13, 5764–5771 (1994).

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Yu, X., Jacobs, S. A., West, S. C., Ogawa, T. & Egelman, E. H. Domain structure and dynamics in the helical filaments formed by RecA and Rad51 on DNA. Proc. Natl Acad. Sci. USA 98, 8419–8424 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Pellegrini, L. et al. Insights into DNA recombination from the structure of a RAD51–BRCA2 complex. Nature 420, 287–293 (2002). Describes the crystal structure of a RAD51–BRC fusion protein, and illustrates how the interaction with a BRC repeat might 'cap' RAD51 in the monomeric form and inhibit nucleoprotein-filament formation.

    CAS  PubMed  Google Scholar 

  6. Mazin, A. V., Zaitseva, E., Sung, P. & Kowalczykowski, S. C. Tailed duplex DNA is the preferred substrate for Rad51 protein-mediated homologous pairing. EMBO J. 19, 1148–1156 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  7. McIlwraith, M. J. et al. Reconstitution of the strand invasion step of double-strand break repair using human RAD51, RAD52 and RPA proteins. J. Mol. Biol. 304, 151–164 (2000).

    CAS  PubMed  Google Scholar 

  8. Benson, F. E., Baumann, P. & West, S. C. Synergistic actions of RAD51 and RAD52 in genetic recombination and DNA repair. Nature 391, 401–404 (1998).

    CAS  PubMed  Google Scholar 

  9. Sung, P. Function of yeast Rad52 protein as a mediator between replication protein-A and the Rad51 recombinase. J. Biol. Chem. 272, 28194–28197 (1997).

    CAS  PubMed  Google Scholar 

  10. New, J. H., Sugiyama, T., Zaitseva, E. & Kowalczykowski, S. C. Rad52 protein stimulates DNA strand exchange by Rad51 and replication protein-A. Nature 391, 407–410 (1998).

    CAS  PubMed  Google Scholar 

  11. Shinohara, A. & Ogawa, T. Stimulation by Rad52 of yeast Rad51-mediated recombination. Nature 391, 404–407 (1998).

    CAS  PubMed  Google Scholar 

  12. Game, J. C. DNA double-strand breaks and the RAD50–RAD57 genes in Saccharomyces. Semin. Cancer Biol. 4, 73–83 (1993).

    CAS  PubMed  Google Scholar 

  13. Milne, G. T. & Weaver, D. T. Dominant-negative alleles of RAD52 reveal a DNA repair recombination complex including Rad51 and Rad52. Genes Dev. 7, 1755–1765 (1993).

    CAS  PubMed  Google Scholar 

  14. Shen, Z. Y., Cloud, K. G., Chen, D. J. & Park, M. S. Specific interactions between the human RAD51 and RAD52 proteins. J. Biol. Chem. 271, 148–152 (1996).

    CAS  PubMed  Google Scholar 

  15. Mortensen, U. H., Bendixen, C., Sunjevaric, I. & Rothstein, R. DNA strand annealing is promoted by the yeast Rad52 protein. Proc. Natl Acad. Sci. USA 93, 10729–10734 (1996). The first evidence that Rad52 protein promotes single-strand-annealing reactions in vitro.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sung, P. Catalysis of ATP-dependent homologous DNA pairing and strand exchange by yeast Rad51 protein. Science 265, 1241–1243 (1994). Shows that Rad51 promotes strand-exchange reactions that are similar to those catalysed by E. coli RecA.

    CAS  PubMed  Google Scholar 

  17. Baumann, P., Benson, F. E. & West, S. C. Human RAD51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro. Cell 87, 757–766 (1996).

    CAS  PubMed  Google Scholar 

  18. Sung, P. & Stratton, S. A. Yeast Rad51 recombinase mediates polar DNA strand exchange in the absence of ATP hydrolysis. J. Biol. Chem. 271, 27983–27986 (1996).

    CAS  PubMed  Google Scholar 

  19. Morrison, C. et al. The essential functions of human RAD51 are independent of ATP hydrolysis. Mol. Cell. Biol. 19, 6891–6897 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Stark, J. M. et al. ATP hydrolysis by mammalian RAD51 has a key role during homology-directed DNA repair. J. Biol. Chem. 277, 20185–20194 (2002).

    CAS  PubMed  Google Scholar 

  21. Petukhova, G., Stratton, S. & Sung, P. Catalysis of homologous DNA pairing by yeast Rad51 and Rad54 proteins. Nature 393, 91–94 (1998).

    CAS  PubMed  Google Scholar 

  22. Van Komen, S., Petukhova, G., Sigurdsson, S., Stratton, S. & Sung, P. Superhelicity-driven homologous DNA pairing by yeast recombination factors Rad51 and Rad54. Mol. Cell 6, 563–572 (2000).

    CAS  PubMed  Google Scholar 

  23. Mazin, A. V., Bornarth, C. J., Solinger, J. A., Heyer, W. -D. & Kowalczykowski, S. C. Rad54 protein is targeted to pairing loci by the Rad51 nucleoprotein filament. Mol. Cell 6, 583–592 (2000).

    CAS  PubMed  Google Scholar 

  24. Solinger, J. A., Lutz, G., Sugiyama, T., Kowalczykowski, S. C. & Heyer, W. D. Rad54 protein stimulates heteroduplex DNA formation in the synaptic phase of DNA strand exchange via specific interactions with the presynaptic Rad51 nucleoprotein filament. J. Mol. Biol. 307, 1207–1221 (2001).

    CAS  PubMed  Google Scholar 

  25. Van Komen, S., Petukhova, G., Sigurdsson, S. & Sung, P. Functional cross-talk among Rad51, Rad54, and replication protein A in heteroduplex DNA joint formation. J. Biol. Chem. 277, 43578–43587 (2002).

    CAS  PubMed  Google Scholar 

  26. Petukhova, G., Van Komen, S., Vergano, S., Klein, H. & Sung, P. Yeast Rad54 promotes Rad51-dependent homologous DNA pairing via ATP hydrolysis-driven change in DNA double helix conformation. J. Biol. Chem. 274, 29453–29462 (1999).

    CAS  PubMed  Google Scholar 

  27. Tan, T. L. R. et al. Mouse RAD54 affects DNA conformation and DNA-damage-induced RAD51 foci formation. Curr. Biol. 9, 325–328 (1999).

    CAS  PubMed  Google Scholar 

  28. Sigurdsson, S., Van Komen, S., Petukhovan, G. & Sung, P. Homologous DNA pairing by human recombination factors RAD51 and RAD54. J. Biol. Chem. 277, 42790–42794 (2002).

    CAS  PubMed  Google Scholar 

  29. Solinger, J. A., Kiianitsa, K. & Heyer, W. D. Rad54, a Swi2/Snf2-like recombinational repair protein, disassembles Rad51:dsDNA filaments. Mol. Cell 10, 1175–1188 (2002).

    CAS  PubMed  Google Scholar 

  30. Paques, F. & Haber, J. E. Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 63, 349–404 (1999). A comprehensive review of recombination pathways and mechanisms in yeast.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Szostak, J. W., Orr-Weaver, T. L., Rothstein, R. J. & Stahl, F. W. The double-strand break repair model for recombination. Cell 33, 25–35 (1983). Describes the prototypic model for repair that is initiated by a double-strand break.

    CAS  PubMed  Google Scholar 

  32. West, S. C. Processing of recombination intermediates by the RuvABC proteins. Annu. Rev. Genet. 31, 213–244 (1997).

    CAS  PubMed  Google Scholar 

  33. Kleff, S., Kemper, B. & Sternglanz, R. Identification and characterization of yeast mutants and the gene for a cruciform cutting endonuclease. EMBO J. 11, 699–704 (1992).

    CAS  PubMed Central  PubMed  Google Scholar 

  34. White, M. F. & Lilley, D. M. J. The structure-selectivity and sequence-preference of the junction-resolving enzyme Cce1 of Saccharomyces cerevisiae. J. Mol. Biol. 257, 330–341 (1996).

    CAS  PubMed  Google Scholar 

  35. Whitby, M. C. & Dixon, J. A new Holliday junction resolving enzyme from Schizosaccharomyces pombe that is homologous to Cce1 from Saccharomyces cerevisiae. J. Mol. Biol. 272, 509–522 (1997).

    CAS  PubMed  Google Scholar 

  36. Oram, M., Keeley, A. & Tsaneva, I. Holliday junction resolvase in Schizosaccharomyces pombe has identical endonuclease activity to the Cce1 homolog Ydc2. Nucleic Acids Res. 26, 594–601 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Constantinou, A., Davies, A. A. & West, S. C. Branch migration and Holliday junction resolution catalyzed by activities from mammalian cells. Cell 104, 259–268 (2001). Shows that mammalian cells have activities that promote coupled branch migration and Holliday junction resolution in reactions that are similar to those catalysed by E. coli RuvABC.

    Article  CAS  PubMed  Google Scholar 

  38. Constantinou, A., Chen, X. -B., McGowan, C. H. & West, S. C. Holliday junction resolution in human cells: two junction endonucleases with distinct substrate specificities. EMBO J. 21, 5577–5585 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Boddy, M. N. et al. Mus81–Eme1 are essential components of a Holliday junction resolvase. Cell 107, 537–548 (2001).

    CAS  PubMed  Google Scholar 

  40. Chen, X. B. et al. Human MUS81-associated endonuclease cleaves Holliday junctions in vitro. Mol. Cell 8, 1117–1127 (2001).

    CAS  PubMed  Google Scholar 

  41. Kaliraman, V., Mullen, J. R., Fricke, W. M., Bastin-Shanower, S. A. & Brill, S. J. Functional overlap between Sgs1–Top3 and the Mms4–Mus81 endonuclease. Genes Dev. 15, 2730–2740 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Doe, C. L., Ahn, J. S., Dixon, J. & Whitby, M. C. Mus81–Eme1 and Rqh1 involvement in processing stalled and collapsed replication forks. J. Biol. Chem. 277, 32753–32759 (2002).

    CAS  PubMed  Google Scholar 

  43. Van Dyck, E., Hajibagheri, N. M. A., Stasiak, A. & West, S. C. Visualisation of human RAD52 protein and its complexes with RAD51 and DNA. J. Mol. Biol. 284, 1027–1038 (1998).

    CAS  PubMed  Google Scholar 

  44. Stasiak, A. Z. et al. The human RAD52 protein exists as a heptameric ring. Curr. Biol. 10, 337–340 (2000).

    CAS  PubMed  Google Scholar 

  45. Shinohara, A., Shinohara, M., Ohta, T., Matsuda, S. & Ogawa, T. Rad52 forms ring structures and cooperates with RPA in single-strand DNA annealing. Genes Cells 3, 145–156 (1998).

    CAS  PubMed  Google Scholar 

  46. Parsons, C. A., Baumann, P., Van Dyck, E. & West, S. C. Precise binding to single-stranded DNA termini by RAD52 protein. EMBO J. 19, 4175–4181 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Kagawa, W., Kurumizaka, H., Ikawa, S., Yokoyama, S. & Shibata, T. Homologous pairing promoted by the human RAD52 protein. J. Biol. Chem. 276, 35201–35208 (2001).

    CAS  PubMed  Google Scholar 

  48. Park, M. S., Ludwig, D. L., Stigger, E. & Lee, S. H. Physical interaction between human RAD52 and RPA is required for homologous recombination in mammalian cells. J. Biol. Chem. 271, 18996–19000 (1996).

    CAS  PubMed  Google Scholar 

  49. Kagawa, W. et al. Crystal structure of the homologous-pairing domain from the human RAD52 recombinase in the undecameric form. Mol. Cell 10, 359–371 (2002).

    CAS  PubMed  Google Scholar 

  50. Singleton, M. R., Wentzell, L. M., Liu, Y., West, S. C. & Wigley, D. B. Structure of the single-strand annealing domain of human RAD52 protein. Proc. Natl Acad. Sci. USA 99, 13492–13497 (2002). References 49 and 50 present the X-ray crystal structure of the single-strand-annealing domain of human RAD52.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Singleton, M. R., Sawaya, M. R., Ellenberger, T. & Wigley, D. B. Crystal structure of T7 gene 4 ring helicase indicates a mechanism for sequential hydrolysis of nucleotides. Cell 101, 589–600 (2000).

    CAS  PubMed  Google Scholar 

  52. Haaf, T., Golub, E. I., Reddy, G., Radding, C. M. & Ward, D. C. Nuclear foci of mammalian RAD51 recombination protein in somatic cells after DNA damage and its localization in synaptonemal complexes. Proc. Natl Acad. Sci. USA 92, 2298–2302 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Scully, R. et al. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90, 425–435 (1997).

    CAS  PubMed  Google Scholar 

  54. Liu, Y. & Maizels, N. Coordinated response of mammalian RAD51 and RAD52 to DNA damage. EMBO Rep. 1, 85–90 (2000).

    PubMed Central  PubMed  Google Scholar 

  55. Lisby, M., Rothstein, R. & Mortensen, U. H. Rad52 forms DNA repair and recombination centers during S phase. Proc. Natl Acad. Sci. USA 98, 8276–8282 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Essers, J. et al. Nuclear dynamics of RAD52 group homologous recombination proteins in response to DNA damage. EMBO J. 21, 2030–2037 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Raderschall, E., Golub, E. I. & Haaf, T. Nuclear foci of mammalian recombination proteins are located at single-stranded DNA regions formed after DNA damage. Proc. Natl Acad. Sci. USA 96, 1921–1926 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Scully, R. et al. Association of BRCA1 with RAD51 in mitotic and meiotic cells. Cell 88, 265–275 (1997).

    CAS  PubMed  Google Scholar 

  59. Chen, J. J. et al. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol. Cell 2, 317–328 (1998). References 58 and 59 show the colocalization of RAD51 recombinase with the BRCA1 and BRCA2 tumour suppressors, leading to the concept that certain inheritable breast cancers might be due to defects in repair by homologous recombination.

    CAS  PubMed  Google Scholar 

  60. Yuan, S. -S. F. et al. BRCA2 is required for ionizing radiation-induced assembly of RAD51 complex in vivo. Cancer Res. 59, 3547–3551 (1999).

    CAS  PubMed  Google Scholar 

  61. Godthelp, B. C., Artwert, F., Joenje, H. & Zdzienicka, M. Z. Impaired DNA damage-induced nuclear RAD51 foci formation uniquely characterizes Fanconi anemia group D1. Oncogene 21, 5002–5005 (2002).

    CAS  PubMed  Google Scholar 

  62. Tashiro, S. et al. S phase specific formation of the human RAD51 protein nuclear foci in lymphocytes. Oncogene 12, 2165–2170 (1996).

    CAS  PubMed  Google Scholar 

  63. Tarsounas, M., Davies, D. & West, S. C. BRCA2-dependent and independent formation of RAD51 nuclear foci. Oncogene 22, 1115–1122 (2003).

    CAS  PubMed  Google Scholar 

  64. Sharan, S. K. et al. Embryonic lethality and radiation hypersensitivity mediated by RAD51 in mice lacking BRCA2. Nature 386, 804–810 (1997).

    CAS  PubMed  Google Scholar 

  65. Wong, A. K. C., Pero, R., Ormonde, P. A., Tavtigian, S. V. & Bartel, P. L. RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene BRCA2. J. Biol. Chem. 272, 31941–31944 (1997).

    CAS  PubMed  Google Scholar 

  66. Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. BRCA1 controls homology-directed DNA repair. Mol. Cell 4, 511–518 (1999).

    CAS  PubMed  Google Scholar 

  67. Moynahan, M. E., Pierce, A. J. & Jasin, M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol. Cell 7, 263–272 (2001).

    CAS  PubMed  Google Scholar 

  68. Xia, F. et al. Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining. Proc. Natl Acad. Sci. USA 98, 8644–8649 (2001). References 67 and 68 provide the first direct evidence that BRCA2 -defective cells are compromised in their ability to promote double-strand-break repair by homologous recombination.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Xu, X. et al. 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 (1999).

    CAS  PubMed  Google Scholar 

  70. Yu, V. P. C. C. et al. Gross chromosomal rearrangements and genetic exchange between non-homologous chromosomes following BRCA2 inactivation. Genes. Dev. 14, 1400–1406 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Rahman, N. & Stratton, M. R. The genetics of breast cancer susceptibility. Annu. Rev. Genet. 32, 95–121 (1998).

    CAS  PubMed  Google Scholar 

  72. Welcsh, P. L. & King, M. C. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum. Mol. Genet. 10, 705–713 (2001).

    CAS  PubMed  Google Scholar 

  73. Kerr, P. & Ashworth, A. New complexities for BRCA1 and BRCA2. Curr. Biol. 11, R668–R676 (2001).

    CAS  PubMed  Google Scholar 

  74. Wang, Y. et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14, 927–939 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Anderson, S. E., Schlegel, B. P., Nakajima, T., Wolpin, E. S. & Parvin, J. D. BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A. Nature Genet. 19, 254–256 (1998).

    CAS  PubMed  Google Scholar 

  76. Yarden, R. I. & Brody, L. C. BRCA1 interacts with components of the histone deacetylase complex. Proc. Natl Acad. Sci. USA 96, 4983–4988 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhong, Q. et al. Association of BRCA1 with the RAD50–MRE11–p95 complex and the DNA damage response. Science 285, 747–750 (1999).

    CAS  PubMed  Google Scholar 

  78. Bochar, D. A. et al. BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell 102, 257–265 (2000).

    CAS  PubMed  Google Scholar 

  79. Marmorstein, L. Y. et al. A human BRCA2 complex containing a structural DNA binding component influences cell cycle progression. Cell 104, 247–257 (2001).

    CAS  PubMed  Google Scholar 

  80. Chiba, N. & Parvin, J. D. Redistribution of BRCA1 among four different protein complexes following replication blockage. J. Biol. Chem. 276, 38549–38554 (2001).

    CAS  PubMed  Google Scholar 

  81. Wu, L. C. et al. Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nature Genet. 14, 430–440 (1996).

    CAS  PubMed  Google Scholar 

  82. Ruffner, H., Joazeiro, C. A. P., Hemmati, D., Hunter, T. & Verma, I. M. Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc. Natl Acad. Sci. USA 98, 5134–5139 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Mallery, D. L., Vandenberg, C. J. & Hiom, K. Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. EMBO J. 21, 6755–6762 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Baer, R. & Ludwig, T. The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity. Curr. Opin. Genet. Dev. 12, 86–91 (2002).

    CAS  PubMed  Google Scholar 

  85. D'Andrea, A. D. & Grompe, M. The Fanconi anaemia/BRCA pathway. Nature Rev. Cancer 3, 23–34 (2002).

    Google Scholar 

  86. Grompe, M. & D'Andrea, A. D. Fanconi anemia and DNA repair. Hum. Mol. Genet. 10, 2253–2259 (2001).

    CAS  PubMed  Google Scholar 

  87. Joenje, H. & Patel, K. J. The emerging genetic and molecular basis of Fanconi anaemia. Nature Rev. Genet. 2, 446–457 (2001).

    CAS  PubMed  Google Scholar 

  88. Garcia-Higuera, I. et al. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol. Cell 7, 249–262 (2001). The first indication of the inter-relationship between Fanconi anaemia and BRCA gene products.

    CAS  PubMed  Google Scholar 

  89. Ekblad, C. M. S. et al. Characterisation of the BRCT domains of the breast cancer susceptibility gene product BRCA1. J. Mol. Biol. 320, 431–442 (2002).

    CAS  PubMed  Google Scholar 

  90. Williams, R. S., Green, R. & Glover, J. N. M. Crystal structure of the BRCT repeat region from the breast cancer-associated protein BRCA1. Nature Struct. Biol. 8, 838–842 (2001).

    CAS  PubMed  Google Scholar 

  91. Cantor, S. B. et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105, 149–160 (2001).

    CAS  PubMed  Google Scholar 

  92. Bork, P., Blomberg, N. & Nilges, M. Internal repeats in the BRCA2 protein sequence. Nature Genet. 13, 22–23 (1996).

    CAS  PubMed  Google Scholar 

  93. Chen, P. L. et al. The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. Proc. Natl Acad. Sci. USA 95, 5287–5292 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Takata, M. et al. Conserved domains in the chicken homologue of BRCA2. Oncogene 21, 1130–1134 (2002).

    CAS  PubMed  Google Scholar 

  95. Kojic, M., Kostrub, C. F., Buchman, A. R. & Holloman, W. K. BRCA2 homolog required for proficiency in DNA repair, recombination, and genome stability in Ustilago maydis. Mol. Cell 10, 683–691 (2002). A BRCA2-like protein found in a smut fungus provides evidence for the universality of BRCA2 and its potential role in the control of RAD51 recombinase.

    CAS  PubMed  Google Scholar 

  96. Chen, C. F., Chen, P. L., Zhong, Q., Sharp, Z. D. & Lee, W. H. Expression of BRC repeats in breast cancer cells disrupts the BRCA2–RAD51 complex and leads to radiation hypersensitivity and loss of G2/M checkpoint control. J. Biol. Chem. 274, 32931–32935 (1999).

    CAS  PubMed  Google Scholar 

  97. Davies, A. A. et al. Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol. Cell 7, 273–282 (2001). The first indication that interactions between RAD51 and a BRC repeat could block nucleoprotein-filament formation and thereby inhibit recombinase activity.

    CAS  PubMed  Google Scholar 

  98. Cortez, D., Wang, Y., Qin, J. & Elledge, S. J. Requirement of ATM-dependent phosphorylation of BRCA1 in the DNA damage response to double-strand breaks. Science 286, 1162–1166 (1999).

    CAS  PubMed  Google Scholar 

  99. Yuan, Z. M. et al. Regulation of RAD51 function by c-Abl in response to DNA damage. J. Biol. Chem. 273, 3799–3802 (1998).

    CAS  PubMed  Google Scholar 

  100. Chen, G. et al. Radiation-induced assembly of RAD51 and RAD52 recombination complex requires ATP and c-Abl. J. Biol. Chem. 274, 12748–12752 (1999).

    CAS  PubMed  Google Scholar 

  101. Saintigny, Y., Dumay, A., Lambert, S. & Lopez, B. S. A novel role for the Bcl-2 protein family: specific suppression of the RAD51 recombination pathway. EMBO J. 20, 2596–2607 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Yang, H. J. et al. BRCA2 function in DNA binding and recombination from a BRCA2–DSS1–ssDNA structure. Science 297, 1837–1848 (2002). Provided the first high-resolution structure of a segment of BRCA2 and showed that BRCA2 has the ability to bind DNA.

    CAS  PubMed  Google Scholar 

  103. Marston, N. J. et al. Interaction between the product of the breast cancer susceptibility gene BRCA2 and DSS1, a protein functionally conserved from yeast to mammals. Mol. Cell. Biol. 19, 4633–4642 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Howlett, N. G. et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297, 606–609 (2002). Showed that the Fanconi anaemia D1 gene ( FANCD1 ) is the same as BRCA2.

    CAS  PubMed  Google Scholar 

  105. Liang, F., Han, M. G., Romanienko, P. J. & Jasin, M. Homology-directed repair is a major double-strand break repair pathway in mammalian cells. Proc. Natl Acad. Sci. USA 95, 5172–5177 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Takata, M. et al. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J. 17, 5497–5508 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Essers, J. et al. Homologous and non-homologous recombination differentially affect DNA damage repair in mice. EMBO J. 19, 1703–1710 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Smith, G. C. M. & Jackson, S. P. The DNA-dependent protein kinase. Genes Dev. 13, 916–934 (1999).

    CAS  PubMed  Google Scholar 

  109. Chu, G. Double-strand break repair. J. Biol. Chem. 272, 24097–24100 (1997).

    CAS  PubMed  Google Scholar 

  110. Critchlow, S. E. & Jackson, S. P. DNA end-joining: from yeast to man. Trends Biochem. Sci. 23, 394–398 (1998).

    CAS  PubMed  Google Scholar 

  111. Kanaar, R., Hoeijmakers, J. H. J. & van Gent, D. C. Molecular mechanisms of DNA double-strand break repair. Trends Cell Biol. 8, 483–489 (1998).

    CAS  PubMed  Google Scholar 

  112. Dynan, W. S. & Yoo, S. Interaction of Ku protein and DNA-dependent protein kinase catalytic subunit with nucleic acids. Nucleic Acids Res. 26, 1551–1559 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Walker, J. R., Corpina, R. A. & Goldberg, J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412, 607–614 (2001).

    CAS  PubMed  Google Scholar 

  114. Hanakahi, L. A., Bartlet-Jones, M., Chappell, C., Pappin, D. & West, S. C. Binding of inositol phosphate to DNA-PK and stimulation of double-strand break repair. Cell 102, 721–729 (2000).

    CAS  PubMed  Google Scholar 

  115. Hanakahi, L. A. & West, S. C. Specific interaction of IP6 with human Ku70/80, the DNA-binding subunit of DNA-PK. EMBO J. 21, 2038–2044 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Ma, Y. M. & Lieber, M. R. Binding of inositol hexakisphosphate (IP6) to Ku but not to DNA-PKcs . J. Biol. Chem. 277, 10756–10759 (2002).

    CAS  PubMed  Google Scholar 

  117. Odom, A. R., Stahlberg, A., Wente, S. R. & York, J. D. A role for nuclear inositol 1,4,5-trisphosphate kinase in transcriptional control. Science 287, 2026–2029 (2000).

    CAS  PubMed  Google Scholar 

  118. York, J. D., Odom, A. R., Murphy, R., Ives, E. B. & Wente, S. R. A phospholipase C-dependent inositol polyphosphate kinase pathway required for efficient messenger RNA export. Science 285, 96–100 (1999).

    CAS  PubMed  Google Scholar 

  119. Steger, D. J., Haswell, E. S., Miller, A. L., Wente, S. R. & O'Shea, E. K. Regulation of chromatin remodelling by inositol polyphosphates. Science 299, 114–116 (2003).

    CAS  PubMed  Google Scholar 

  120. Shen, X., Xiao, H., Ranallo, R., Wu, W. -H. & Wu, C. Modulation of ATP-dependent chromatin-remodeling complexes by inositol polyphosphates. Science 299, 112–114 (2003).

    CAS  PubMed  Google Scholar 

  121. Yamada, K. et al. Crystal structure of the RuvA–RuvB complex: a structural basis for the Holliday junction migrating motor machinery. Mol. Cell 10, 671–681 (2002).

    CAS  PubMed  Google Scholar 

  122. Parsons, C. A., Stasiak, A., Bennett, R. J. & West, S. C. Structure of a multisubunit complex that promotes DNA branch migration. Nature 374, 375–378 (1995). The first visualization of the E. coli RuvAB–Holliday-junction complex, which led to the proposal of a model for branch migration mediated by two opposing motor proteins.

    CAS  PubMed  Google Scholar 

  123. Rafferty, J. B. et al. Crystal structure of DNA recombination protein RuvA and a model for its binding to the Holliday junction. Science 274, 415–421 (1996).

    CAS  PubMed  Google Scholar 

  124. Hargreaves, D. et al. Crystal structure of E. coli RuvA with bound DNA Holliday junction at 6Å resolution. Nature Struct. Biol. 5, 441–446 (1998).

    CAS  PubMed  Google Scholar 

  125. Roe, S. M. et al. Crystal structure of an octameric RuvA–Holliday junction complex. Mol. Cell 2, 361–372 (1998).

    CAS  PubMed  Google Scholar 

  126. Ariyoshi, M., Nishino, T., Iwasaki, H., Shinagawa, H. & Morikawa, K. Crystal structure of the Holliday junction DNA in complex with a single RuvA tetramer. Proc. Natl Acad. Sci. USA 97, 8257–8262 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Yamada, K. et al. Crystal structure of the Holliday junction migration motor protein RuvB from Thermus thermophilus HB8. Proc. Natl Acad. Sci. USA 98, 1442–1447 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Ingleston, S. M., Sharples, G. J. & Lloyd, R. G. The acidic pin of RuvA modulates Holliday junction binding and processing by the RuvABC resolvasome. EMBO J. 19, 6266–6274 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Whitby, M. C., Bolt, E. L., Chan, S. N. & Lloyd, R. G. Interactions between RuvA and RuvC at Holliday junctions: inhibition of junction cleavage and formation of a RuvA–RuvC–DNA complex. J. Mol. Biol. 264, 878–890 (1996).

    CAS  PubMed  Google Scholar 

  130. van Gool, A. J., Shah, R., Mézard, C. & West, S. C. Functional interactions between the Holliday junction resolvase and the branch migration motor of Escherichia coli. EMBO J. 17, 1838–1845 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Interthal, H. & Heyer, W. D. MUS81 encodes a novel helix-hairpin-helix protein involved in the response to UV- and methylation-induced DNA damage in Saccharomyces cerevisiae. Mol. Gen. Genet. 263, 812–827 (2000).

    CAS  PubMed  Google Scholar 

  132. Boddy, M. N. et al. Damage tolerance protein Mus81 associates with the FHA1 domain of checkpoint kinase Cds1. Mol. Cell. Biol. 20, 8758–8766 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Mullen, J. R., Kaliraman, V., Ibrahim, S. S. & Brill, S. J. Requirement for three novel protein complexes in the absence of the Sgs1 DNA helicase in Saccharomyces cerevisiae. Genetics 157, 103–118 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  134. West, S. C. The RuvABC proteins and Holliday junction processing in Escherichia coli. J. Bacteriol. 178, 1237–1241 (1996).

    CAS  PubMed Central  PubMed  Google Scholar 

  135. de los Santos, T., Loidl, J., Larkin, B. & Hollingsworth, N. M. A role for MMS4 in the processing of recombination intermediates during meiosis in Saccharomyces cerevisiae. Genetics 159, 1511–1525 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Ranatunga, W. et al. Human RAD52 exhibits two modes of self-association. J. Biol. Chem. 276, 15876–15880 (2001).

    CAS  PubMed  Google Scholar 

  137. Lloyd, J. A., Fiorget, A. L. & Knight, K. L. Correlation of biochemical properties with the oligomeric state of human RAD52 protein. J. Biol. Chem. 277, 46172–46178 (2002).

    CAS  PubMed  Google Scholar 

  138. Houtsmuller, A. B. et al. Action of DNA repair endonuclease ERCC1/XPF in living cells. Science 284, 958–961 (1999).

    CAS  PubMed  Google Scholar 

  139. West, S. C. Cross-links between Fanconi anaemia and BRCA2. DNA Repair (Amst.) 2, 281–284 (2003).

    Google Scholar 

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Acknowledgements

I thank the members of my laboratory, past and present, for their help in formulating many of the concepts that are presented in this review, and apologize to the many authors whose work it was not possible to include owing to space constraints. Work in the Genetic Recombination Laboratory is supported by Cancer Research UK and the Swiss Bridge Fund.

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Authors and Affiliations

  1. Cancer Research UK, London Research Institute, Clare Hall Laboratories, South Mimms, EN6 3LD, Hertfordshire, UK

    Stephen C. West

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DATABASES

InterPro

BRCT

LocusLink

BRCA1

BRCA2

FANCA

FANCB

FANCC

FANCD1

FANCD2

FANCE

FANCF

FANCG

RPA

Swiss-Prot

BACH1

BARD1

DNA ligase IV

DNA-PKcs

Ku70

Ku80

Mus81

MRE11

NBS1

RAD50

RAD51

RAD52

RAD54

XRCC4

FURTHER INFORMATION

Stephen C. West's laboratory

Glossary

HOMOLOGOUS PAIRING

Interactions between DNA molecules of similar sequence.

STRAND EXCHANGE

The transfer of a strand of DNA from one molecule to another.

RECOMBINASES

Proteins that promote DNA–DNA interactions.

NUCLEOLYTIC RESECTION

The trimming back of one strand of DNA.

SWI2/SNF2

SWI/SNF proteins are DNA-dependent ATPases that modulate protein–DNA interactions.

NEGATIVE SUPERCOIL

The twisting or underwinding of DNA resulting in its compaction.

HOLLIDAY JUNCTION

A crossover structure that links recombining DNAs.

DNA LIGASE

An enzyme that seals nicks in duplex DNA.

HYDROXYL RADICAL

A small chemical probe that attacks deoxyribose residues in the DNA backbone.

RING-FINGER DOMAIN

A loop structure that is found in more than 200 proteins.

E3 UBIQUITIN LIGASE

Protein ubiquitylation is important for protein activation or degradation. The E3 ligase attaches ubiquitin to the protein that has been targeted for degradation.

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West, S. Molecular views of recombination proteins and their control. Nat Rev Mol Cell Biol 4, 435–445 (2003). https://doi.org/10.1038/nrm1127

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