Genomic Instability in Cancer Development

  • Penny A. Jeggo
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 570)


Telomere Length Replication Fork Genomic Stability Cancer Predisposition Nijmegen Breakage Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Alderton, G.K., Joenje, H., Varon, R., Borglum, A.D., Jeggo, P.A. and O’Driscoll, M. 2004 Seckel syndrome exhibits cellular features demonstrating defects in the ATR signalling pathway. Hum. Mol. Genet. in press.Google Scholar
  2. Alt, F.W., E.M. Oltz, F. Young, J. Gorman, G. Taccioli, and J. Chen. 1992. VDJ recombination. Immunology Today. 13:306–314.CrossRefPubMedGoogle Scholar
  3. Bailey, S.M., M.N. Cornforth, A. Kurimasa, D.J. Chen, and E.H. Goodwin. 2001. Strand-specific postreplicative processing of mammalian telomeres. Science. 293:2462–5.CrossRefPubMedGoogle Scholar
  4. Bailey, S.M., M.N. Cornforth, R.L. Ullrich, and E.H. Goodwin. 2004. Dysfunctional mammalian telomeres join with DNA double-strand breaks. DNA Repair (Amst). 3:349–57.Google Scholar
  5. Bailey, S.M., J. Meyne, D.J. Chen, A. Kurimasa, G.C. Li, B.E. Lehnert, and E.H. Goodwin. 1999. DNA double-strand break repair proteins are required to cap the ends of mammalian chromosomes. Proceedings of the National Academy of Sciences of the United States of America. 96:14899–14904.CrossRefPubMedGoogle Scholar
  6. Barlow, C., S. Hirotsune, R. Paylor, M. Liyanage, M. Eckhaus, F. Collins, Y. Shiloh, J.N. Crawley, T. Ried, D. Tagle, and A. Wynshaw-Boris. 1996. Atm-deficient mice: a paradigm of ataxia-telangiectasia. Cell. 86:159–171.CrossRefPubMedGoogle Scholar
  7. Barnes, D.E., G. Stamp, I. Rosewell, A. Denzel, and T. Lindahl. 1998. Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice. Current Biology. 8:1395–1398.CrossRefPubMedGoogle Scholar
  8. Bassing, C.H., and F.W. Alt. 2004. The cellular response to general and programmed DNA double strand breaks. DNA Repair (Amst). 3:781–96.Google Scholar
  9. Blier, P.R., A.J. Griffith, J. Craft, and J.A. Hardin. 1993. Binding of Ku protein to DNA. Measurement of affinity for ends and demonstration of binding to nicks. Journal of Biological Chemistry. 268:7594–7601.PubMedGoogle Scholar
  10. Boulton, S.J., and S.P. Jackson. 1996. Identification of a Saccharomyces cerevisiae Ku80 homologue: roles in DNA double-strand break repair and in telomeric maintenance. Nucleic Acids Research. 24:4639–4648.CrossRefPubMedGoogle Scholar
  11. Boulton, S.J., and S.P. Jackson. 1998. Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing. EMBO Journal. 17:1819–1828.CrossRefPubMedGoogle Scholar
  12. Calsou, P., C. Delteil, P. Frit, J. Drouet, and B. Salles. 2003. Coordinated assembly of Ku and p460 subunits of the DNA-dependent protein kinase on DNA ends is necessary for XRCC4-ligase IV recruitment. J Mol Biol. 326:93–103.CrossRefPubMedGoogle Scholar
  13. Carney, J.P., R.S. Maser, H. Olivares, E.M. Davis, M. Le Beau, J.R. Yates III, L. Hays, W.F. Morgan, and J.H.J. Petrini. 1998. The hMre11/hRad50 protein complex and Nijmegen breakage-syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell. 93:477–486.CrossRefPubMedGoogle Scholar
  14. Casper, A.M., P. Nghiem, M.F. Arlt, and T.W. Glover. 2002. ATR regulates fragile site stability. Cell. 111:779–789.CrossRefPubMedGoogle Scholar
  15. Cohen, H.Y., S. Lavu, K.J. Bitterman, B. Hekking, T.A. Imahiyerobo, C. Miller, R. Frye, H. Ploegh, B.M. Kessler, and D.A. Sinclair. 2004. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell. 13:627–38.CrossRefPubMedGoogle Scholar
  16. Connor, F., D. Bertwistle, P.J. Mee, G.M. Ross, S. Swift, E. Grigorieva, V.L. Tybulewicz, and A. Ashworth. 1997. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nature Genetics. 17:423–430.CrossRefPubMedGoogle Scholar
  17. Cox, M.M., M.F. Goodman, K.N. Kreuzer, D.J. Sherratt, S.J. Sandler, and M.K. J. 2000. The importance of repairing stalled replication forks. Nature. 404:37–41.PubMedGoogle Scholar
  18. Custer, R.P., G.C. Bosma, and M.J. Bosma. 1985. Severe combined immunodeficiency (SCID) in the mouse: Pathology, reconstitution, neoplasms. American Journal of Pathology. 120:464–477.PubMedGoogle Scholar
  19. d’Adda di Fagagna, F., M.P. Hande, W.M. Tong, D. Roth, P.M. Lansdorp, Z.Q. Wang, and S.P. Jackson. 2001. Effects of DNA nonhomologous end-joining factors on telomere length and chromosomal stability in mammalian cells. Curr Biol. 11:1192–6.Google Scholar
  20. Davies, A.A., J.Y. Masson, M.J. McIlwraith, A.Z. Stasiak, A. Stasiak, A.R. Venkitaraman, and S.C. West. 2001. Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol Cell. 7:273–282.CrossRefPubMedGoogle Scholar
  21. de Vries, E., W. van Driel, W.G. Bergsma, A.C. Arnberg, and P.C. van der Vliet. 1989. HeLa nuclear protein recognizing DNA termini and translocating on DNA forming a regular DNA-multimeric protein complex. Journal of Molecular Biology. 208:65–78.PubMedGoogle Scholar
  22. Deans, B., C.S. Griffin, M. Maconochie, and J. Thacker. 2000. Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice. EMBO J. 19:6675–6685.CrossRefPubMedGoogle Scholar
  23. Deans, B., C.S. Griffin, P. O’Regan, M. Jasin, and J. Thacker. 2003. Homologous recombination deficiency leads to profound genetic instability in cells derived from Xrcc2-knockout mice. Cancer Res. 63:8181–7.PubMedGoogle Scholar
  24. Difilippantonio, M.J., J. Zhu, H.T. Chen, E. Meffre, M.C. Nussenzweig, E.E. Max, T. Ried, and A. Nussenzweig. 2000a. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature. 404:510–514.CrossRefPubMedGoogle Scholar
  25. Difilippantonio, M.J., J. Zhu, H.T. Chen, E. Meffre, M.C. Nussenzweig, E.E. Max, T. Ried, and A. Nussenzweig. 2000b. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation [In Process Citation]. Nature. 404:510–514.CrossRefPubMedGoogle Scholar
  26. Dvir, A., S.R. Peterson, M.W. Knuth, H. Lu, and W.S. Dynan. 1992. Ku autoantigen is the regulatory component of a template-associated protein kinase that phosphorylates RNA polymerase II. Proceedings of the National Academy of Sciences of the United States of America. 89:11920–11924.PubMedGoogle Scholar
  27. Espejel, S., S. Franco, S. Rodriguez-Perales, S.D. Bouffler, J.C. Cigudosa, and M.A. Blasco. 2002. Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres. EMBO J. 21:2207–19.PubMedGoogle Scholar
  28. Espejel, S., M. Martin, P. Klatt, J. Martin-Caballero, J.M. Flores, and M.A. Blasco. 2004. Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice. Embo Rep. 5:503–9.CrossRefPubMedGoogle Scholar
  29. Ferguson, D.O., J.M. Sekiguchi, S. Chang, K.M. Frank, Y. Gao, R.A. DePinho, and F.W. Alt. 2000. The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations. Proc Natl Acad Sci U S A. 97:6630–3.PubMedGoogle Scholar
  30. Foray, N., D. Marot, A. Gabriel, V. Randrianarison, A. Carr, M. Perricaudet, A. Ashworth, and P. Jeggo. 2003. A subset of ATM and ATR-dependent phosphorylation events requires the BRCA1 protein. EMBO. 22:2860–2871.Google Scholar
  31. Frank, K.M., N.E. Sharpless, Y. Gao, J.M. Sekiguchi, D.O. Ferguson, C. Zhu, J.P. Manis, J. Horner, R.A. DePinho, and F.W. Alt. 2000. DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol Cell. 5:993–1002.CrossRefPubMedGoogle Scholar
  32. Gao, Y., D.O. Ferguson, W. Xie, J.P. Manis, J. Sekiguchi, K.M. Frank, J. Chaudhuri, J. Horner, R.A. DePinho, and F.W. Alt. 2000. Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature. 404:897–900.CrossRefPubMedGoogle Scholar
  33. Gilley, D., H. Tanaka, M.P. Hande, A. Kurimasa, G.C. Li, M. Oshimura, and D.J. Chen. 2001. DNA-PKcs is critical for telomere capping. Proc Natl Acad Sci U S A. 98:15084–8.CrossRefPubMedGoogle Scholar
  34. Girard, P.-M., B. Kysela, C.J. Harer, A.J. Doherty, and P.A. Jeggo. 2004. Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms. Human Molecular Genetics:In press.Google Scholar
  35. Girard, P.-M., E. Riballo, A. Begg, A. Waugh, and P.A. Jeggo. 2002. Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest. Oncogene. 21:4191–4199.CrossRefPubMedGoogle Scholar
  36. Gladdy, R.A., M.D. Taylor, C.J. Williams, I. Grandal, J. Karaskova, J.A. Squire, J.T. Rutka, C.J. Guidos, and J.S. Danska. 2003. The RAG-1/2 endonuclease causes genomic instability and controls CNS complications of lymphoblastic leukemia in p53/Prkdc-deficient mice. Cancer Cell. 3:37–50.CrossRefPubMedGoogle Scholar
  37. Gottlieb, T.M., and S.P. Jackson. 1993. The DNA-dependent protein kinase: requirement of DNA ends and association with Ku Antigen. Cell. 72:131–142.CrossRefPubMedGoogle Scholar
  38. Goytisolo, F.A., E. Samper, S. Edmonson, G.E. Taccioli, and M.A. Blasco. 2001. The absence of the dna-dependent protein kinase catalytic subunit in mice results in anaphase bridges and in increased telomeric fusions with normal telomere length and G-strand overhang. Mol Cell Biol. 21:3642–51.CrossRefPubMedGoogle Scholar
  39. Gravel, S., M. Larrivee, P. Labrecque, and R.J. Wellinger. 1998. Yeast Ku as a regulator of chromosomal DNA end structure. Science. 280:741–744.CrossRefPubMedGoogle Scholar
  40. Gravel, S., and R.J. Wellinger. 2002. Maintenance of double-stranded telomeric repeats as the critical determinant for cell viability in yeast cells lacking Ku. Mol Cell Biol. 22:2182–93.CrossRefPubMedGoogle Scholar
  41. Griffin, C.S., P.J. Simpson, C.R. Wilson, and J. Thacker. 2000. Mammalian recombination-repair genes XRCC2 and XRCC3 promote correct chromosome segregation. Nat Cell Biol. 2:757–61.PubMedGoogle Scholar
  42. Gu, Y.S., K.J. Seidl, G.A. Rathbun, C.M. Zhu, J.P. Manis, N. van der Stoep, L. Davidson, H.L. Cheng, J.M. Sekiguchi, K. Frank, P. StanhopeBaker, M.S. Schlissel, D.B. Roth, and F.W. Alt. 1997. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity. 7:653–665.CrossRefPubMedGoogle Scholar
  43. Helleday, T. 2003. Pathways for mitotic homologous recombination in mammalian cells. Mutat Res. 532:103–115.PubMedGoogle Scholar
  44. Herrmann, G., T. Lindahl, and P. Schar. 1998. Saccharomyces cerevisiae LIF1: a function involved in DNA double-strand break repair related to mammalian XRCC4. EMBO Journal. 17:4188–4198.CrossRefPubMedGoogle Scholar
  45. Hiom, K., and M. Gellert. 1997. A stable RAG1-RAG2-DNA complex that is active in V(D)J cleavage. Cell. 88:65–72.CrossRefPubMedGoogle Scholar
  46. Hirsch, B., A. Shimamura, L. Moreau, S. Baldinger, M. Hag-alshiekh, B. Bostrom, S. Sencer, and A.D. D’Andrea. 2004. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood. 103:2554–9.CrossRefPubMedGoogle Scholar
  47. Howlett, N.G., T. Taniguchi, S. Olson, B. Cox, Q. Waisfisz, C. De Die-Smulders, N. Persky, M. Grompe, H. Joenje, G. Pals, H. Ikeda, E.A. Fox, and A.D. D’Andrea. 2002. Biallelic Inactivation of BRCA2 in Fanconi Anemia. Science. 13:13.Google Scholar
  48. Hsu, H.L., D. Gilley, E.H. Blackburn, and D.J. Chen. 1999. Ku is associated with the telomere in mammals. Proc Natl Acad Sci U S A. 96:12454–8.PubMedGoogle Scholar
  49. International Nijmegen Breakage Syndrome Study Group. 2000. Nijmegen breakage syndrome. The International Nijmegen Breakage Syndrome Study Group. Arch Dis Child. 82:400–406.Google Scholar
  50. Jeggo, P.A. 1998. DNA breakage and repair. Advances in Genetics. 38:185–211.PubMedCrossRefGoogle Scholar
  51. Jeggo, P.A. 2004. The mechanism of DNA non-homologous end-joining: Lessons learned from biophysical, biochemical and cellular studies. In Eukaryotic DNA damage surveillance and repair. K.W. Caldecott, editor. and Kluwer Academic/Plenum Publishers. 146–158.Google Scholar
  52. Jeggo, P.A., A.M. Carr, and A.R. Lehmann. 1998. Splitting the ATM: distinct repair and checkpoint defects in ataxia-telangiectasia. Trends in Genetics. 14:312–316.CrossRefPubMedGoogle Scholar
  53. Jhappan, C., H.C. Morse, 3rd, R.D. Fleischmann, M.M. Gottesman, and G. Merlino. 1997. DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus. Nat Genet. 17:483–6.CrossRefPubMedGoogle Scholar
  54. Johnson, R.D., and M. Jasin. 2000. Sister chromatid gene conversion is a prominent double-strand break repair pathway in mammalian cells. EMBO J. 19:3398–3407.CrossRefPubMedGoogle Scholar
  55. Johnson, R.D., N. Liu, and M. Jasin. 1999. Mammalian XRCC2 promotes the repair of DNA double-strand breaks by homologous recombination. Nature. 401:397–399.CrossRefPubMedGoogle Scholar
  56. Jones, N.J., R. Cox, and J. Thacker. 1987. Isolation and cross-sensitivity of X-ray-sensitive mutants of V79-4 hamster cells. Mutation Research. 183:279–286.PubMedGoogle Scholar
  57. Kanaar, R., J.H. Hoeijmakers, and D.C. van Gent. 1998. Molecular mechanisms of DNA double strand break repair. Trends Cell Biol. 8:483–489.CrossRefPubMedGoogle Scholar
  58. Karanjawala, Z.E., U. Grawunder, C.L. Hsieh, and M.R. Lieber. 1999. The nonhomologous DNA end joining pathway is important for chromosome stability in primary fibroblasts. Curr Biol. 9:1501–1504.CrossRefPubMedGoogle Scholar
  59. Kemp, L.M., and P.A. Jeggo. 1986. Radiation-induced chromosome damage in X-ray-sensitive mutants (xrs) of the Chinese hamster ovary cell line. Mutat Res. 166:255–263.PubMedGoogle Scholar
  60. Kim, S.T., B. Xu, and M.B. Kastan. 2002. Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage. Genes Dev. 16:560–570.CrossRefPubMedGoogle Scholar
  61. King, M.C., J.H. Marks, and J.B. Mandell. 2003. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 302:643–6.CrossRefPubMedGoogle Scholar
  62. Kraakman-van der Zwet, M., W.W. Wiegant, and M.Z. Zdzienicka. 2003. Brca2 (XRCC11) deficiency results in enhanced mutagenesis. Mutagenesis. 18:521–5.Google Scholar
  63. Kuhne, M., E. Riballo, N. Rief, K. Rothkamm, P.A. Jeggo, and M. Lobrich. 2004. A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity. Cancer Res. 64:500–508.CrossRefPubMedGoogle Scholar
  64. Kurimasa, A., S. Kumano, N. Boubnov, M.D. Story, C. Tung, S.R. Peterson, and D.J. Chen. 1999. Requirement for the kinase activity of human DNA-dependent protein kinase catalytic subunit in DNA strand break rejoining. Molecular and Cellular Biology. 19:3877–3884.PubMedGoogle Scholar
  65. Laroche, T., S.G. Martin, M. Gotta, H.C. Gorham, F.E. Pryde, E.J. Louis, and S.M. Gasser. 1998. Mutation of yeast Ku genes disrupts the subnuclear organization of telomeres. Current Biology. 8:653–656.CrossRefPubMedGoogle Scholar
  66. Latre, L., L. Tusell, M. Martin, R. Miro, J. Egozcue, M.A. Blasco, and A. Genesca. 2003. Shortened telomeres join to DNA breaks interfering with their correct repair. Exp Cell Res. 287:282–288.CrossRefPubMedGoogle Scholar
  67. Lee, H., A.H. Trainer, L.S. Friedman, F.C. Thistlethwaite, M.J. Evans, B.A. Ponder, and A.R. Venkitaraman. 1999. Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2. Mol Cell. 4:1–10.CrossRefPubMedGoogle Scholar
  68. Lee, J.H., and T.T. Paull. 2004. Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science. 304:93–6.PubMedGoogle Scholar
  69. Li, G.C., H. Ouyang, X. Li, H. Nagasawa, J.B. Little, D.J. Chen, C.C. Ling, Z. Fuks, and C. Cordon-Cardo. 1998. Ku70: a candidate tumor suppressor gene for murine T cell lymphoma. Molecular and Cellular Biology. 2:1–8.Google Scholar
  70. Lim, D.-S., and P. Hasty. 1996. A mutation in mouse rad51results in an early embryonic lethal that is suppressed by a mutation in p53. Molecular and Cellular Biology. 16:7133–7143.PubMedGoogle Scholar
  71. Lim, D.S., H. Vogel, D.M. Willerford, A.T. Sands, K.A. Platt, and P. Hasty. 2000. Analysis of ku80-mutant mice and cells with deficient levels of p53. Mol Cell Biol. 20:3772–80.CrossRefPubMedGoogle Scholar
  72. Lio, Y.C., A.V. Mazin, S.C. Kowalczykowski, and D.J. Chen. 2003. Complex formation by the human Rad51B and Rad51C DNA repair proteins and their activities in vitro. J Biol Chem. 278:2469–78.CrossRefPubMedGoogle Scholar
  73. Liu, Y., J.Y. Masson, R. Shah, P. O’Regan, and S.C. West. 2004. RAD51C is required for Holliday junction processing in mammalian cells. Science. 303:243–246.CrossRefPubMedGoogle Scholar
  74. Ma, Y., U. Pannicke, K. Schwarz, and M.R. Lieber. 2002. Hairpin Opening and Overhang Processing by an Artemis/DNA-Dependent Protein Kinase Complex in Nonhomologous End Joining and V(D)J Recombination. Cell. 108:781–794.CrossRefPubMedGoogle Scholar
  75. Masson, J.Y., M.C. Tarsounas, A.Z. Stasiak, A. Stasiak, R. Shah, M.J. McIlwraith, F.E. Benson, and S.C. West. 2001. Identification and purification of two distinct complexes containing the five RAD51 paralogs. Genes Dev. 15:3296–307.CrossRefPubMedGoogle Scholar
  76. Mills, K.D., D.O. Ferguson, and F.W. Alt. 2003. The role of DNA breaks in genomic instability and tumorigenesis. Immunol Rev. 194:77–95.CrossRefPubMedGoogle Scholar
  77. Moshous, D., C. Pannetier, R. Chasseval Rd, F. Deist Fl, M. Cavazzana-Calvo, S. Romana, E. Macintyre, D. Canioni, N. Brousse, A. Fischer, J.L. Casanova, and J.P. Villartay. 2003. Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J Clin Invest. 111:381–387.CrossRefPubMedGoogle Scholar
  78. Moynahan, M.E., J.W. Chiu, B.H. Koller, and M. Jasin. 1999. Brca1 controls homology-directed DNA repair. Mol Cell. 4:511–518.CrossRefPubMedGoogle Scholar
  79. Moynahan, M.E., A.J. Pierce, and M. Jasin. 2001. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 7:263–272.CrossRefPubMedGoogle Scholar
  80. Myung, K., G. Ghosh, F.J. Fattah, G Li, H. Kim, A. Dutia, E. Pak, S. Smith, and E.A. Hendrickson. 2004. Regulation of telomere length and suppression of genomic instability in human somatic cells by Ku86. Mol Cell Biol. 24:5050–9.CrossRefPubMedGoogle Scholar
  81. Nikjoo, H., P. O’Neill, W.E. Wilson, and D.T. Goodhead. 2001. Computational approach for determining the spectrum of DNA damage induced by ionizing radiation. Radiat Res. 156:577–583.PubMedGoogle Scholar
  82. O’Driscoll, M., K.M. Cerosaletti, P.-M. Girard, Y. Dai, M. Stumm, B. Kysela, B. Hirsch, A. Gennery, S.E. Palmer, J. Seidel, R.A. Gatti, R. Varon, M.A. Oettinger, K. Sperling, P.A. Jeggo, and P. Concannon. 2001. DNA Ligase IV mutations identified in patients exhibiting development delay and immunodeficiency. Molecular Cell. 8:1175–1185.PubMedGoogle Scholar
  83. Patel, K.J., V.P. Yu, H. Lee, A. Corcoran, F.C. Thistlethwaite, M.J. Evans, W.H. Colledge, L.S. Friedman, B.A. Ponder, and A.R. Venkitaraman. 1998. Involvement of Brca2 in DNA repair. Mol Cell. 1:347–57.CrossRefPubMedGoogle Scholar
  84. Pellegrini, L., D.S. Yu, T. Lo, S. Anand, M. Lee, T.L. Blundell, and A.R. Venkitaraman. 2002. Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature. 420:287–293.CrossRefPubMedGoogle Scholar
  85. Perrault, R., H. Wang, M. Wang, B. Rosidi, and G. Iliakis. 2004. Backup pathways of NHEJ are suppressed by DNA-PK. J Cell Biochem. 92:781–94.CrossRefPubMedGoogle Scholar
  86. Peterson, S.E., A.E. Stellwagen, S.J. Diede, M.S. Singer, Z.W. Haimberger, C.O. Johnson, M. Tzoneva, and D.E. Gottschling. 2001. The function of a stem-loop in telomerase RNA is linked to the DNA repair protein Ku. Nat Genet. 27:64–7.PubMedGoogle Scholar
  87. Petrini, J.H. 1999. The Mammalian Mre11-Rad50-nbs1 Protein Complex: Integration of functions in the cellular DNA damage response. Am J Hum Genet. 64:1264–1269.CrossRefPubMedGoogle Scholar
  88. Petukhova, G., S. Stratton, and P. Sung. 1998. Catalysis of homologous dna pairing by yeast rad51 and rad 54 proteins. Nature. 393:91–94.PubMedGoogle Scholar
  89. Pierce, A.J., R.D. Johnson, L.H. Thompson, and M. Jasin. 1999. XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. Genes Dev. 13:2633–2638.CrossRefPubMedGoogle Scholar
  90. Riballo, E., S.E. Critchlow, S.H. Teo, A.J. Doherty, A. Priestley, B. Broughton, B. Kysela, H. Beamish, N. Plowman, C.F. Arlett, A.R. Lehmann, S.P. Jackson, and P.A. Jeggo. 1999. Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Current Biology. 19:699–702.Google Scholar
  91. Richardson, C., N. Horikoshi, and T.K. Pandita. 2004. The role of the DNA double-strand break response network in meiosis. DNA Repair (Amst). 3:1149–64.Google Scholar
  92. Rooney, S., J. Sekiguchi, S. Whitlow, M. Eckersdorff, J.P. Manis, C. Lee, D.O. Ferguson, and F.W. Alt. 2004. Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells. Proc Natl Acad Sci U S A. 101:2410–5.CrossRefPubMedGoogle Scholar
  93. Rooney, S., J. Sekiguchi, C. Zhu, H.L. Cheng, J. Manis, S. Whitlow, J. DeVido, D. Foy, J. Chaudhuri, D. Lombard, and F.W. Alt. 2002. Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. Mol Cell. 10:1379–1390.CrossRefPubMedGoogle Scholar
  94. Rothkamm, K., I. Kruger, L.H. Thompson, and M. Lobrich. 2003. Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol. 23:5706–5715.CrossRefPubMedGoogle Scholar
  95. Rouse, J., and S.P. Jackson. 2002. Interfaces between the detection, signaling, and repair of DNA damage. Science. 297:547–551.CrossRefPubMedGoogle Scholar
  96. Samper, E., Goytisolo, F.A., Slijepcevic, P., van Buul, P.P. and M.A. Blasco. 2000 Mammalian Ku86 protein prevents telomeric fusions independently of the length of TTAGGG repeats and the G-strand overhang. EMBO Rep, 1:244–52.CrossRefPubMedGoogle Scholar
  97. Sawada, M., W. Sun, P. Hayes, K. Leskov, D.A. Boothman, and S. Matsuyama. 2003. Ku70 suppresses the apoptotic translocation of Bax to mitochondria. Nat Cell Biol. 5:320–9.PubMedGoogle Scholar
  98. Sharan, S.K., M. Morimatsu, U. Albrecht, D.-S. Lim, E. Regel, C. Dinh, A. Sands, G. Eichele, P. Hasty, and A. Bradley. 1997. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature. 386:804–810.CrossRefPubMedGoogle Scholar
  99. Shiloh, Y. 2001. ATM and ATR: networking cellular responses to DNA damage. Curr Opin Genet Dev. 11:71–77.CrossRefPubMedGoogle Scholar
  100. Shiloh, Y. 2003. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer. 3(155–168.CrossRefPubMedGoogle Scholar
  101. Shivji, M.K., and A.R. Venkitaraman. 2004. DNA recombination, chromosomal stability and carcinogenesis: insights into the role of BRCA2. DNA Repair (Amst). 3:835–43.Google Scholar
  102. Sigurdsson, S., S. Van Komen, W. Bussen, D. Schild, J.S. Albala, and P. Sung. 2001. Mediator function of the human Rad51B-Rad51C complex in Rad51/RPA-catalyzed DNA strand exchange. Genes Dev. 15:3308–18.CrossRefPubMedGoogle Scholar
  103. Smith, G.C., and S.P. Jackson. 1999. The DNA-dependent protein kinase. Genes Dev. 13:916–934.PubMedGoogle Scholar
  104. Snouwaert, J.N., L.C. Gowen, A.M. Latour, A.R. Mohn, A. Xiao, L. DiBiase, and B.H. Koller. 1999. BRCA1 deficient embryonic stem cells display a decreased homologous recombination frequency and an increased frequency of non-homologous recombination that is corrected by expression of a brca1 transgene. Oncogene. 18:7900–7.PubMedGoogle Scholar
  105. Stellwagen, A.E., Z.W. Haimberger, J.R. Veatch, and D.E. Gottschling. 2003. Ku interacts with telomerase RNA to promote telomere addition at native and broken chromosome ends. Genes Dev. 17:2384–95.CrossRefPubMedGoogle Scholar
  106. Stewart, G.S., R.S. Maser, T. Stankovic, D.A. Bressan, M.I. Kaplan, N.G. Jaspers, A. Raams, P.J. Byrd, J.H. Petrini, and A.M. Taylor. 1999. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell. 99:577–587.CrossRefPubMedGoogle Scholar
  107. Struewing, J.P., P. Hartge, S. Wacholder, S.M. Baker, M. Berlin, M. McAdams, M.M. Timmerman, L.C. Brody, and M.A. Tucker. 1997. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 336:1401–8.CrossRefPubMedGoogle Scholar
  108. Taylor, A.M.R. 1992. Aataxia-telangiectasia genes and predisposition to leukaemia, lymphoma and breast cancer. British Journal of Cancer. 66:5–9.PubMedGoogle Scholar
  109. Teo, S.-H., and S.P. Jackson. 1997. Identification of Saccharomyces cerevisiae DNA ligase IV: involvement in DNA double-strand break repair. EMBO Journal. 16:4788–4795.CrossRefPubMedGoogle Scholar
  110. Thacker, J., A.N. Ganesh, A. Stretch, D.M. Benjamin, A.J. Zahalsky, and E.A. Hendrickson. 1994. Gene mutation and V(D)J recombination in the radiosensitive irs lines. Mutagenesis. 9:163–168.PubMedGoogle Scholar
  111. Thompson, D., and D.F. Easton. 2002. Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 94:1358–65.PubMedGoogle Scholar
  112. Thompson, L.H., and C.L. Limoli. 2004. Origin, recognition, signaling and repair of DNA double-strand breaks in mammalian cells. In Eukaryotic DNA damage surveillance and repair. K.W. Caldecott, editor. Landes Bioscience/, Texas. 107–145.Google Scholar
  113. Thompson, L.H., and D. Schild. 2001. Homologous recombinational repair of DNA ensures mammalian chromosome stability. Mutat Res. 477:131–153.PubMedGoogle Scholar
  114. Thorlacius, S., G. Olafsdottir, L. Tryggvadottir, S. Neuhausen, J.G. Jonasson, S.V. Tavtigian, H. Tulinius, H.M. Ogmundsdottir, and J.E. Eyfjord. 1996. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet. 13:117–9.CrossRefPubMedGoogle Scholar
  115. Tsukamoto, Y., J. Kato, and H. Ikeda. 1997. Silencing factors participate in DNA repair and recombination in Saccharomyces cerevisiae. Nature. 388:900–903.PubMedGoogle Scholar
  116. Tsuzuki, T., Y. Fujii, K. Sakumi, Y. Tominaga, K. Nakao, M. Sekiguchi, A. Matsushiro, Y. Yoshimura, and T. Morita. 1996. Targeted disruption of the Rad51 gene leads to lethality in embryonic mice. Proceedings of the National Academy of Sciences of the United States of America. 93:6236–6240.CrossRefPubMedGoogle Scholar
  117. Tucker, J.D., N.J. Jones, N.A. Allen, J.L. Minkler, L.H. Thompson, and A.V. Carrano. 1991. Cytogenetic characterisation of the ionizing radiation-sensitive Chinese hamster mutant irs1. Mutation Research. 254:143–152.PubMedGoogle Scholar
  118. Tutt, A., A. Gabriel, D. Bertwistle, F. Connor, H. Paterson, J. Peacock, G. Ross, and A. Ashworth. 1999. Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification. Curr Biol. 9:1107–10.CrossRefPubMedGoogle Scholar
  119. van Gent, D.C., J.H. Hoeijmakers, and R. Kanaar. 2001. Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet. 2:196–206.PubMedGoogle Scholar
  120. Varon, R., C. Vissinga, M. Platzer, K.M. Cerosaletti, K.H. Chrzanowska, K. Saar, G. Beckmann, E. Seemanova, P.R. Cooper, N.J. Nowak, M. Stumm, C.M.R. Weemaes, R.A. Gatti, R.K. Wilson, M. Digweed, A. Rosenthal, K. Sperling, P. Concannon, and A. Reis. 1998. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell. 93:467–476.CrossRefPubMedGoogle Scholar
  121. Venkitaraman, A.R. 2002. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 108:171–182.CrossRefPubMedGoogle Scholar
  122. Walker, J.R., R.A. Corpina, and J. Goldberg. 2001. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature. 412:607–614.CrossRefPubMedGoogle Scholar
  123. Wang, H., A.R. Perrault, Y. Takeda, W. Qin, and G. Iliakis. 2003. Biochemical evidence for Ku-independent backup pathways of NHEJ. Nucleic Acids Res. 31:5377–88.PubMedGoogle Scholar
  124. Wold, M.S. 1997. Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism. Annu Rev Biochem. 66:61–92.CrossRefPubMedGoogle Scholar
  125. Xu, B., S. Kim, and M.B. Kastan. 2001. Involvement of brca1 in s-phase and g(2)-phase checkpoints after ionizing irradiation. Mol Cell Biol. 21:3445–3450.PubMedGoogle Scholar
  126. Xu, X., Z. Weaver, S.P. Linke, C. Li, J. Gotay, X.W. Wang, C.C. Harris, T. Ried, and C.X. Deng. 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.PubMedGoogle Scholar
  127. Xu, Y., T. Ashley, E.E. Brainerd, R.T. Bronson, M.S. Meyn, and D. Baltimore. 1996. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects and thymic lymphoma. Genes and Development. 10:2411–2422.PubMedGoogle Scholar
  128. Yarden, R.I., S. Pardo-Reoyo, M. Sgagias, K.H. Cowan, and L.C. Brody. 2002. BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nat Genet. 30:285–289.CrossRefPubMedGoogle Scholar
  129. Yoshihara, T., M. Ishida, A. Kinomura, M. Katsura, T. Tsuruga, S. Tashiro, T. Asahara, and K. Miyagawa. 2004. XRCC3 deficiency results in a defect in recombination and increased endoreduplication in human cells. EMBO J. 23:670–80.CrossRefPubMedGoogle Scholar
  130. Yu, D.S., E. Sonoda, S. Takeda, C.L. Huang, L. Pellegrini, T.L. Blundell, and A.R. Venkitaraman. 2003. Dynamic control of Rad51 recombinase by self-association and interaction with BRCA2. Mol Cell. 12:1029–1041.CrossRefPubMedGoogle Scholar
  131. Yu, V.P., M. Koehler, C. Steinlein, M. Schmid, L.A. Hanakahi, A.J. van Gool, S.C. West, and A.R. Venkitaraman. 2000. Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation. Genes Dev. 14:1400–6.PubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Penny A. Jeggo
    • 1
  1. 1.Genome Damage and Stability CentreUniversity of SussexBrightonUK

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