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Mouse Models of DNA Double Strand Break Repair Deficiency and Cancer

  • Sachin Katyal
  • Peter J. McKinnonEmail author
Chapter

Abstract

Understanding the physiological requirements for DNA repair is of paramount importance in establishing the links between genotoxic stress, development and disease. Defective DNA repair can lead to a variety of systemic pathology including cancer, neurodegeneration and immune defects. The genetically modified mouse is a critical resource for analysis of the effects of genotoxic stress and the tissue-specific requirements for DNA repair pathways. In the following we will outline how mouse models have aided our understanding of the connections between genotoxic stress and cancer and how they will contribute to therapeutic approaches for cancer treatment.

Keywords

Fanconi Anemia Embryonic Lethality Double Strand Break Repair Nijmegen Breakage Syndrome Bloom 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.

References

  1. 1.
    Ahnesorg P, Smith P, Jackson SP (2006) XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124(2): 301–313PubMedCrossRefGoogle Scholar
  2. 2.
    Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, Wynshaw-Boris A (1996) Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86(1): 159–171PubMedCrossRefGoogle Scholar
  3. 3.
    Barnes DE, Stamp G, Rosewell I, Denzel A, Lindahl T (1998) Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice. Curr Biol 8(25): 1395–1398PubMedCrossRefGoogle Scholar
  4. 4.
    Bassing CH, Alt FW (2004) The cellular response to general and programmed DNA double strand breaks. DNA Repair (Amst) 3, (8–9): 781–796CrossRefGoogle Scholar
  5. 5.
    Bassing CH, Suh H, Ferguson DO, Chua KF, Manis J, Eckersdorff M, Gleason M, Bronson R, Lee C, Alt FW (2003) Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114(3): 359–370PubMedCrossRefGoogle Scholar
  6. 6.
    Bates B, Rios M, Trumpp A, Chen C, Fan G, Bishop JM, Jaenisch R (1999) Neurotrophin-3 is required for proper cerebellar development. Nat Neurosci 2(2): 115–117PubMedCrossRefGoogle Scholar
  7. 7.
    Bensaad K, Vousden KH (2005) Savior and slayer: the two faces of p53. Nat Med 11(12): 1278–1279PubMedCrossRefGoogle Scholar
  8. 8.
    Bishop AJ, Barlow C, Wynshaw-Boris AJ, Schiestl RH (2000) Atm deficiency causes an increased frequency of intrachromosomal homologous recombination in mice. Cancer Res 60(2): 395–399PubMedGoogle Scholar
  9. 9.
    Borghesani PR, Alt FW, Bottaro A, Davidson L, Aksoy S, Rathbun GA, Roberts TM, Swat W, Segal RA, Gu Y (2000) Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc Natl Acad Sci USA 97(7): 3336–3341PubMedCrossRefGoogle Scholar
  10. 10.
    Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, Goodyear LJ, Kahn CR (1998) A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 2(5): 559–569PubMedCrossRefGoogle Scholar
  11. 11.
    Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434(7035): 913–917PubMedCrossRefGoogle Scholar
  12. 12.
    Buck D, Malivert L, de Chasseval R, Barraud A, Fondaneche MC, Sanal O, Plebani A, Stephan JL, Hufnagel M, le Deist F, Fischer A, Durandy A, de Villartay JP, Revy P (2006) Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124(2): 287–299PubMedCrossRefGoogle Scholar
  13. 13.
    Burma S, Chen DJ (2004) Role of DNA-PK in the cellular response to DNA double-strand breaks. DNA Repair (Amst) 3 (8–9): 909–918CrossRefGoogle Scholar
  14. 14.
    Campsall KD, Mazerolle CJ, De Repentingy Y, Kothary R, Wallace VA (2002) Characterization of transgene expression and Cre recombinase activity in a panel of Thy-1 promoter-Cre transgenic mice. Dev Dyn 224(2): 135–143PubMedCrossRefGoogle Scholar
  15. 15.
    Celeste A, Difilippantonio S, Difilippantonio MJ, Fernandez-Capetillo O, Pilch DR, Sedelnikova OA, Eckhaus M, Ried T, Bonner WM, Nussenzweig A (2003a) H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114(3): 371–383PubMedCrossRefGoogle Scholar
  16. 16.
    Celeste A, Fernandez-Capetillo O, Kruhlak MJ, Pilch DR, Staudt DW, Lee A, Bonner RF, Bonner WM, Nussenzweig A (2003b) Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat Cell Biol 5(7): 675–679PubMedCrossRefGoogle Scholar
  17. 17.
    Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA, Reina-San-Martin B, Coppola V, Meffre E, Difilippantonio MJ, Redon C, Pilch DR, Olaru A, Eckhaus M, Camerini-Otero RD, Tessarollo L, Livak F, Manova K, Bonner WM, Nussenzweig MC, Nussenzweig A (2002) Genomic instability in mice lacking histone H2AX. Science 296(5569): 922–927PubMedCrossRefGoogle Scholar
  18. 18.
    Chester N, Kuo F, Kozak C, O’Hara CD, Leder P (1998) Stage-specific apoptosis, developmental delay, and embryonic lethality in mice homozygous for a targeted disruption in the murine Bloom’s syndrome gene. Genes Dev 12(21): 3382–3393PubMedCrossRefGoogle Scholar
  19. 19.
    Connor F, Bertwistle D, Mee PJ, Ross GM, Swift S, Grigorieva E, Tybulewicz VL, Ashworth A (1997) Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat Genet 17(4): 423–430PubMedCrossRefGoogle Scholar
  20. 20.
    Cressman VL, Backlund DC, Avrutskaya AV, Leadon SA, Godfrey V, Koller BH (1999a) Growth retardation, DNA repair defects, and lack of spermatogenesis in BRCA1-deficient mice. Mol Cell Biol 19(10): 7061–7075PubMedGoogle Scholar
  21. 21.
    Cressman VL, Backlund DC, Hicks EM, Gowen LC, Godfrey V, Koller BH (1999b) Mammary tumor formation in p53- and BRCA1-deficient mice. Cell Growth Differ 10(1): 1–10PubMedGoogle Scholar
  22. 22.
    D’Andrea AD, Grompe M (2003) The Fanconi anaemia/BRCA pathway. Nat Rev Cancer 3(1): 23–34PubMedCrossRefGoogle Scholar
  23. 23.
    Dacquin R, Starbuck M, Schinke T, Karsenty G (2002) Mouse alpha1(I)-collagen promoter is the best known promoter to drive efficient Cre recombinase expression in osteoblast. Dev Dyn 224(2): 245–251PubMedCrossRefGoogle Scholar
  24. 24.
    Deans B, Griffin CS, Maconochie M, Thacker J (2000) Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice. Embo J 19(24): 6675–6685PubMedCrossRefGoogle Scholar
  25. 25.
    Deans B, Griffin CS, O’Regan P, Jasin M, Thacker J (2003) Homologous recombination deficiency leads to profound genetic instability in cells derived from Xrcc2-knockout mice. Cancer Res 63(23): 8181–8187PubMedGoogle Scholar
  26. 26.
    Demuth I, Frappart PO, Hildebrand G, Melchers A, Lobitz S, Stockl L, Varon R, Herceg Z, Sperling K, Wang ZQ, Digweed M (2004) An inducible null mutant murine model of Nijmegen breakage syndrome proves the essential function of NBS1 in chromosomal stability and cell viability. Hum Mol Genet 13(20): 2385–2397PubMedCrossRefGoogle Scholar
  27. 27.
    Difilippantonio MJ, Zhu J, Chen HT, Meffre E, Nussenzweig MC, Max EE, Ried T, Nussenzweig A (2000) DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 404(6777): 510–514PubMedCrossRefGoogle Scholar
  28. 28.
    Elson A, Wang Y, Daugherty CJ, Morton CC, Zhou F, Campos-Torres J, Leder P (1996) Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc Natl Acad Sci USA 93(23): 13084–13089PubMedCrossRefGoogle Scholar
  29. 29.
    Esashi F, Christ N, Gannon J, Liu Y, Hunt T, Jasin M, West SC (2005) CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 434(7033): 598–604PubMedCrossRefGoogle Scholar
  30. 30.
    Essers J, Hendriks RW, Swagemakers SM, Troelstra C, de Wit J, Bootsma D, Hoeijmakers JH, Kanaar R (1997) Disruption of mouse RAD54 reduces ionizing radiation resistance and homologous recombination. Cell 89(2): 195–204PubMedCrossRefGoogle Scholar
  31. 31.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035): 917–921PubMedCrossRefGoogle Scholar
  32. 32.
    Forde A, Constien R, Grone HJ, Hammerling G, Arnold B (2002) Temporal Cre-mediated recombination exclusively in endothelial cells using Tie2 regulatory elements. Genesis 33(4): 191–197PubMedCrossRefGoogle Scholar
  33. 33.
    Frank KM, Sekiguchi JM, Seidl KJ, Swat W, Rathbun GA, Cheng HL, Davidson L, Kangaloo L, Alt FW (1998) Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 396(6707): 173–177PubMedCrossRefGoogle Scholar
  34. 34.
    Frank KM, Sharpless NE, Gao Y, Sekiguchi JM, Ferguson DO, Zhu C, Manis JP, Horner J, DePinho RA, Alt FW (2000) DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol Cell 5(6): 993–1002PubMedCrossRefGoogle Scholar
  35. 35.
    Frappart PO, Lee Y, Lamont J, McKinnon PJ (2007) BRCA2 is required for neurogenesis and suppression of medulloblastoma. Embo J 26(11): 2732–2742PubMedCrossRefGoogle Scholar
  36. 36.
    Frappart PO, McKinnon PJ (2006) Ataxia-telangiectasia and related diseases. Neuromolecular Med 8(4): 495–511PubMedCrossRefGoogle Scholar
  37. 37.
    Friedberg EC, Meira LB (2006) Database of mouse strains carrying targeted mutations in genes affecting biological responses to DNA damage Version 7. DNA Repair (Amst) 5(2): 189–209CrossRefGoogle Scholar
  38. 38.
    Friedman LS, Thistlethwaite FC, Patel KJ, Yu VP, Lee H, Venkitaraman AR, Abel KJ, Carlton MB, Hunter SM, Colledge WH, Evans MJ, Ponder BA (1998) Thymic lymphomas in mice with a truncating mutation in Brca2. Cancer Res 58(7): 1338–1343PubMedGoogle Scholar
  39. 39.
    Gao Y, Chaudhuri J, Zhu C, Davidson L, Weaver DT, Alt FW (1998) A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination. Immunity 9(3): 367–376PubMedCrossRefGoogle Scholar
  40. 40.
    Gao Y, Ferguson DO, Xie W, Manis JP, Sekiguchi J, Frank KM, Chaudhuri J, Horner J, DePinho RA, Alt FW (2000) Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 404(6780): 897–900PubMedCrossRefGoogle Scholar
  41. 41.
    Gao Y, Sun Y, Frank KM, Dikkes P, Fujiwara Y, Seidl KJ, Sekiguchi JM, Rathbun GA, Swat W, Wang J, Bronson RT, Malynn BA, Bryans M, Zhu C, Chaudhuri J, Davidson L, Ferrini R, Stamato T, Orkin SH, Greenberg ME, Alt FW (1998) A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95(7): 891–902PubMedCrossRefGoogle Scholar
  42. 42.
    Gaveriaux-Ruff C, Kieffer BL (2007) Conditional gene targeting in the mouse nervous system: Insights into brain function and diseases. Pharmacol Ther 113(3): 619–634PubMedCrossRefGoogle Scholar
  43. 43.
    Gayther SA, Mangion J, Russell P, Seal S, Barfoot R, Ponder BA, Stratton MR, Easton D (1997) Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 15(1): 103–105PubMedCrossRefGoogle Scholar
  44. 44.
    Gelman DM, Noain D, Avale ME, Otero V, Low MJ, Rubinstein M (2003) Transgenic mice engineered to target Cre/loxP-mediated DNA recombination into catecholaminergic neurons. Genesis 36(4): 196–202PubMedCrossRefGoogle Scholar
  45. 45.
    Gilbertson RJ, Ellison DW (2008) The origins of medulloblastoma subtypes. Annu Rev Pathol 3: 341–365PubMedCrossRefGoogle Scholar
  46. 46.
    Goss KH, Risinger MA, Kordich JJ, Sanz MM, Straughen JE, Slovek LE, Capobianco AJ, German J, Boivin GP, Groden J (2002) Enhanced tumor formation in mice heterozygous for Blm mutation. Science 297(5589): 2051–2053PubMedCrossRefGoogle Scholar
  47. 47.
    Gowen LC, Johnson BL, Latour AM, Sulik KK, Koller BH (1996) Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nat Genet 12(2): 191–194PubMedCrossRefGoogle Scholar
  48. 48.
    Gu Y, Jin S, Gao Y, Weaver DT, Alt FW (1997) Ku70-deficient embryonic stem cells have increased ionizing radiosensitivity, defective DNA end-binding activity, and inability to support V(D)J recombination. Proc Natl Acad Sci USA 94(15): 8076–8081PubMedCrossRefGoogle Scholar
  49. 49.
    Gu Y, Seidl KJ, Rathbun GA, Zhu C, Manis JP, van der Stoep N, Davidson L, Cheng HL, Sekiguchi JM, Frank K, Stanhope-Baker P, Schlissel MS, Roth DB, Alt FW (1997) Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 7(5): 653–665PubMedCrossRefGoogle Scholar
  50. 50.
    Gurley KE, Kemp CJ (2001) Synthetic lethality between mutation in Atm and DNA-PK(cs) during murine embryogenesis. Curr Biol 11(3): 191–194PubMedCrossRefGoogle Scholar
  51. 51.
    Gustafsson E, Brakebusch C, Hietanen K, Fassler R (2001) Tie-1-directed expression of Cre recombinase in endothelial cells of embryoid bodies and transgenic mice. J Cell Sci 114 (Pt 4): 671–676PubMedGoogle Scholar
  52. 52.
    Helleday T, Lo J, van Gent DC, Engelward BP (2007) DNA double-strand break repair: from mechanistic understanding to cancer treatment. DNA Repair (Amst) 6(7): 923–935CrossRefGoogle Scholar
  53. 53.
    Herzog KH, Chong MJ, Kapsetaki M, Morgan JI, McKinnon PJ (1998) Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system. Science 280(5366): 1089–1091PubMedCrossRefGoogle Scholar
  54. 54.
    Hickson ID (2003) RecQ helicases: caretakers of the genome. Nat Rev Cancer 3(3): 169–178PubMedCrossRefGoogle Scholar
  55. 55.
    Hisahara S, Araki T, Sugiyama F, Yagami K, Suzuki M, Abe K, Yamamura K, Miyazaki J, Momoi T, Saruta T, Bernard CC, Okano H, Miura M (2000) Targeted expression of baculovirus p35 caspase inhibitor in oligodendrocytes protects mice against autoimmune-mediated demyelination. EMBO J 19(3): 341–348PubMedCrossRefGoogle Scholar
  56. 56.
    Holcomb VB, Vogel H, Marple T, Kornegay RW, Hasty P (2006) Ku80 and p53 suppress medulloblastoma that arise independent of Rag-1-induced DSBs. Oncogene 25: 7159–7165PubMedCrossRefGoogle Scholar
  57. 57.
    Isaka F, Ishibashi M, Taki W, Hashimoto N, Nakanishi S, Kageyama R (1999) Ectopic expression of the bHLH gene Math1 disturbs neural development. Eur J Neurosci 11(7): 2582–2588PubMedCrossRefGoogle Scholar
  58. 58.
    Jhappan C, Morse HC, 3rd, Fleischmann RD, Gottesman MM, Merlino G (1997) DNA-PKcs: a T-cell tumour suppressor encoded at the mouse scid locus. Nat Genet 17(4): 483–486PubMedCrossRefGoogle Scholar
  59. 59.
    Jonkers J, Berns A (2002) Conditional mouse models of sporadic cancer. Nat Rev Cancer 2(4): 251–265PubMedCrossRefGoogle Scholar
  60. 60.
    Jonkers J, Meuwissen R, van der Gulden H, Peterse H, van der Valk M, Berns A (2001) Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet 29(4): 418–425PubMedCrossRefGoogle Scholar
  61. 61.
    Kang J, Bronson RT, Xu Y (2002) Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair. Embo J 21(6): 1447–1455PubMedCrossRefGoogle Scholar
  62. 62.
    Karlsson A, Deb-Basu D, Cherry A, Turner S, Ford J, Felsher DW (2003) Defective double-strand DNA break repair and chromosomal translocations by MYC overexpression. Proc Natl Acad Sci USA 100(17): 9974–9979PubMedCrossRefGoogle Scholar
  63. 63.
    Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432(7015): 316–323PubMedCrossRefGoogle Scholar
  64. 64.
    Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW (1991) Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51(23 Pt 1): 6304–6311PubMedGoogle Scholar
  65. 65.
    Kurimasa A, Ouyang H, Dong LJ, Wang S, Li X, Cordon-Cardo C, Chen DJ, Li GC (1999) Catalytic subunit of DNA-dependent protein kinase: impact on lymphocyte development and tumorigenesis. Proc Natl Acad Sci USA 96(4): 1403–1408PubMedCrossRefGoogle Scholar
  66. 66.
    Kuznetsov S, Pellegrini M, Shuda K, Fernandez-Capetillo O, Liu Y, Martin BK, Burkett S, Southon E, Pati D, Tessarollo L, West SC, Donovan PJ, Nussenzweig A, Sharan SK (2007) RAD51C deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females. J Cell Biol 176(5): 581–592PubMedCrossRefGoogle Scholar
  67. 67.
    Lebel M, Leder P (1998) A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity. Proc Natl Acad Sci USA 95(22): 13097–13102PubMedCrossRefGoogle Scholar
  68. 68.
    Lee Y, Barnes DE, Lindahl T, McKinnon PJ (2000) Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm. Genes Dev 14(20): 2576–2580PubMedCrossRefGoogle Scholar
  69. 69.
    Lee Y, McKinnon PJ (2002) DNA ligase IV suppresses medulloblastoma formation. Cancer Res 62(22): 6395–6399PubMedGoogle Scholar
  70. 70.
    Lee Y, McKinnon PJ (2007) Responding to DNA double strand breaks in the nervous system. Neuroscience 145(4): 1365–1374PubMedCrossRefGoogle Scholar
  71. 71.
    Lees-Miller SP, Meek K (2003) Repair of DNA double strand breaks by non-homologous end joining. Biochimie 85(11): 1161–1173PubMedCrossRefGoogle Scholar
  72. 72.
    Li G, Alt FW, Cheng HL, Brush JW, Goff PH, Murphy MM, Franco S, Zhang Y, Zha S (2008) Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V(D)J recombination. Mol Cell 31(5): 631–640PubMedCrossRefGoogle Scholar
  73. 73.
    Li H, Vogel H, Holcomb VB, Gu Y, Hasty P (2007) Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer. Mol Cell Biol 27(23): 8205–8214PubMedCrossRefGoogle Scholar
  74. 74.
    Lieber MR, Ma Y, Pannicke U, Schwarz K (2003) Mechanism and regulation of human non-homologous DNA end-joining. Nat Rev Mol Cell Biol 4(9): 712–720PubMedCrossRefGoogle Scholar
  75. 75.
    Lim DS, Hasty P (1996) A mutation in mouse rad51 results in an early embryonic lethal that is suppressed by a mutation in p53. Mol Cell Biol 16(12): 7133–7143PubMedGoogle Scholar
  76. 76.
    Liu CY, Flesken-Nikitin A, Li S, Zeng Y, Lee WH (1996) Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development. Genes Dev 10(14): 1835–1843PubMedCrossRefGoogle Scholar
  77. 77.
    Liyanage M, Weaver Z, Barlow C, Coleman A, Pankratz DG, Anderson S, Wynshaw-Boris A, Ried T (2000) Abnormal rearrangement within the alpha/delta T-cell receptor locus in lymphomas from Atm-deficient mice. Blood 96(5): 1940–1946PubMedGoogle Scholar
  78. 78.
    Lozano G, Liu G (1998) Mouse models dissect the role of p53 in cancer and development. Semin Cancer Biol 8(5): 337–344PubMedCrossRefGoogle Scholar
  79. 79.
    Lozano G, Zambetti GP (2005) What have animal models taught us about the p53 pathway? J Pathol 205(2): 206–220PubMedCrossRefGoogle Scholar
  80. 80.
    Luo G, Santoro IM, McDaniel LD, Nishijima I, Mills M, Youssoufian H, Vogel H, Schultz RA, Bradley A (2000) Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nat Genet 26(4): 424–429PubMedCrossRefGoogle Scholar
  81. 81.
    McCormack MP, Forster A, Drynan L, Pannell R, Rabbitts TH (2003) The LMO2 T-cell oncogene is activated via chromosomal translocations or retroviral insertion during gene therapy but has no mandatory role in normal T-cell development. Mol Cell Biol 23(24): 9003–9013PubMedCrossRefGoogle Scholar
  82. 82.
    McKinnon PJ (2004) ATM and ataxia telangiectasia. EMBO Rep 5(8): 772–776PubMedCrossRefGoogle Scholar
  83. 83.
    Menisser-de Murcia J, Mark M, Wendling O, Wynshaw-Boris A, de Murcia G (2001) Early embryonic lethality in PARP-1 Atm double-mutant mice suggests a functional synergy in cell proliferation during development. Mol Cell Biol 21(5): 1828–1832CrossRefGoogle Scholar
  84. 84.
    Minichiello L, Korte M, Wolfer D, Kuhn R, Unsicker K, Cestari V, Rossi-Arnaud C, Lipp HP, Bonhoeffer T, Klein R (1999) Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24(2): 401–414PubMedCrossRefGoogle Scholar
  85. 85.
    Minn AJ, Boise LH, Thompson CB (1996) Expression of Bcl-xL and loss of p53 can cooperate to overcome a cell cycle checkpoint induced by mitotic spindle damage. Genes Dev 10(20): 2621–2631PubMedCrossRefGoogle Scholar
  86. 86.
    Nussenzweig A, Chen C, da Costa Soares V, Sanchez M, Sokol K, Nussenzweig MC, Li GC (1996) Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature 382(6591): 551–555PubMedCrossRefGoogle Scholar
  87. 87.
    Nussenzweig A, Sokol K, Burgman P, Li L, Li GC (1997) Hypersensitivity of Ku80-deficient cell lines and mice to DNA damage: the effects of ionizing radiation on growth, survival, and development. Proc Natl Acad Sci USA 94(25): 13588–13593PubMedCrossRefGoogle Scholar
  88. 88.
    O’Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, Hirsch B, Gennery A, Palmer SE, Seidel J, Gatti RA, Varon R, Oettinger MA, Neitzel H, Jeggo PA, Concannon P (2001) DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell 8(6): 1175–1185PubMedCrossRefGoogle Scholar
  89. 89.
    O’Driscoll M, Gennery AR, Seidel J, Concannon P, Jeggo PA (2004) An overview of three new disorders associated with genetic instability: LIG4 syndrome, RS-SCID and ATR-Seckel syndrome. DNA Repair (Amst) 3(8–9): 1227–1235CrossRefGoogle Scholar
  90. 90.
    Offit K, Levran O, Mullaney B, Mah K, Nafa K, Batish SD, Diotti R, Schneider H, Deffenbaugh A, Scholl T, Proud VK, Robson M, Norton L, Ellis N, Hanenberg H, Auerbach AD (2003) Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J Natl Cancer Inst 95(20): 1548–1551PubMedGoogle Scholar
  91. 91.
    Orii KE, Lee Y, Kondo N, McKinnon PJ (2006) Selective utilization of nonhomologous end-joining and homologous recombination DNA repair pathways during nervous system development. Proc Natl Acad Sci USA 103(26): 10017–10022PubMedCrossRefGoogle Scholar
  92. 92.
    Ouyang H, Nussenzweig A, Kurimasa A, Soares VC, Li X, Cordon-Cardo C, Li W, Cheong N, Nussenzweig M, Iliakis G, Chen DJ, Li GC (1997) Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination In vivo. J Exp Med 186(6): 921–929PubMedCrossRefGoogle Scholar
  93. 93.
    Parant JM, Lozano G (2003) Disrupting TP53 in mouse models of human cancers. Hum Mutat 21(3): 321–326PubMedCrossRefGoogle Scholar
  94. 94.
    Patel KJ, Yu VP, Lee H, Corcoran A, Thistlethwaite FC, Evans MJ, Colledge WH, Friedman LS, Ponder BA, Venkitaraman AR (1998) Involvement of Brca2 in DNA repair. Mol Cell 1(3): 347–357PubMedCrossRefGoogle Scholar
  95. 95.
    Pittman DL, Schimenti JC (2000) Midgestation lethality in mice deficient for the RecA-related gene, Rad51d/Rad51l3. Genesis 26(3): 167–173PubMedCrossRefGoogle Scholar
  96. 96.
    Postic C, Magnuson MA (2000) DNA excision in liver by an albumin-Cre transgene occurs progressively with age. Genesis 26(2): 149–150PubMedCrossRefGoogle Scholar
  97. 97.
    Postic C, Shiota M, Niswender KD, Jetton TL, Chen Y, Moates JM, Shelton KD, Lindner J, Cherrington AD, Magnuson MA (1999) Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J Biol Chem 274(1): 305–315PubMedCrossRefGoogle Scholar
  98. 98.
    Rickert RC, Roes J, Rajewsky K (1997) B lymphocyte-specific, Cre-mediated mutagenesis in mice. Nucleic Acids Res 25(6): 1317–1318PubMedCrossRefGoogle Scholar
  99. 99.
    Rijkers T, Van Den Ouweland J, Morolli B, Rolink AG, Baarends WM, Van Sloun PP, Lohman PH, Pastink A (1998) Targeted inactivation of mouse RAD52 reduces homologous recombination but not resistance to ionizing radiation. Mol Cell Biol 18(11): 6423–6429PubMedGoogle Scholar
  100. 100.
    Rohlmann A, Gotthardt M, Hammer RE, Herz J (1998) Inducible inactivation of hepatic LRP gene by Cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants. J Clin Invest 101(3): 689–695PubMedCrossRefGoogle Scholar
  101. 101.
    Rooney S, Alt FW, Lombard D, Whitlow S, Eckersdorff M, Fleming J, Fugmann S, Ferguson DO, Schatz DG, Sekiguchi J (2003) Defective DNA repair and increased genomic instability in Artemis-deficient murine cells. J Exp Med 197(5): 553–565PubMedCrossRefGoogle Scholar
  102. 102.
    Rooney S, Sekiguchi J, Zhu C, Cheng HL, Manis J, Whitlow S, DeVido J, Foy D, Chaudhuri J, Lombard D, Alt FW (2002) Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. Mol Cell 10(6): 1379–1390PubMedCrossRefGoogle Scholar
  103. 103.
    Sedelnikova OA, Pilch DR, Redon C, Bonner WM (2003) Histone H2AX in DNA damage and repair. Cancer Biol Ther 2(3): 233–235PubMedGoogle Scholar
  104. 104.
    Sekiguchi J, Ferguson DO, Chen HT, Yang EM, Earle J, Frank K, Whitlow S, Gu Y, Xu Y, Nussenzweig A, Alt FW (2001) Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development. Proc Natl Acad Sci USA 98(6): 3243–3248PubMedCrossRefGoogle Scholar
  105. 105.
    Sharan SK, Morimatsu M, Albrecht U, Lim DS, Regel E, Dinh C, Sands A, Eichele G, Hasty P, Bradley A (1997) Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386(6627): 804–810PubMedCrossRefGoogle Scholar
  106. 106.
    Shen SX, Weaver Z, Xu X, Li C, Weinstein M, Chen L, Guan XY, Ried T, Deng CX (1998) A targeted disruption of the murine Brca1 gene causes gamma-irradiation hypersensitivity and genetic instability. Oncogene 17(24): 3115–3124PubMedCrossRefGoogle Scholar
  107. 107.
    Shiloh Y (2003) ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3(3): 155–168PubMedCrossRefGoogle Scholar
  108. 108.
    Shiloh Y (2006) The ATM-mediated DNA-damage response: taking shape. Trends Biochem Sci 31(7): 402–410PubMedCrossRefGoogle Scholar
  109. 109.
    Shu Z, Smith S, Wang L, Rice MC, Kmiec EB (1999) Disruption of muREC2/RAD51L1 in mice results in early embryonic lethality which can Be partially rescued in a p53(–/–) background. Mol Cell Biol 19(12): 8686–8693PubMedGoogle Scholar
  110. 110.
    Spring K, Cross S, Li C, Watters D, Ben-Senior L, Waring P, Ahangari F, Lu SL, Chen P, Misko I, Paterson C, Kay G, Smorodinsky NI, Shiloh Y, Lavin MF (2001) Atm knock-in mice harboring an in-frame deletion corresponding to the human ATM 7636del9 common mutation exhibit a variant phenotype. Cancer Res 61(11): 4561–4568PubMedGoogle Scholar
  111. 111.
    Suzuki A, de la Pompa JL, Hakem R, Elia A, Yoshida R, Mo R, Nishina H, Chuang T, Wakeham A, Itie A, Koo W, Billia P, Ho A, Fukumoto M, Hui CC, Mak TW (1997) Brca2 is required for embryonic cellular proliferation in the mouse. Genes Dev 11(10): 1242–1252PubMedCrossRefGoogle Scholar
  112. 112.
    Taub R, Kirsch I, Morton C, Lenoir G, Swan D, Tronick S, Aaronson S, Leder P (1982) Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci USA 79(24): 7837–7841PubMedCrossRefGoogle Scholar
  113. 113.
    Tsuzuki T, Fujii Y, Sakumi K, Tominaga Y, Nakao K, Sekiguchi M, Matsushiro A, Yoshimura Y, Morita T (1996) Targeted disruption of the Rad51 gene leads to lethality in embryonic mice. Proc Natl Acad Sci USA 93(13): 6236–6240PubMedCrossRefGoogle Scholar
  114. 114.
    van Gent DC, van der Burg M (2007) Non-homologous end-joining, a sticky affair. Oncogene 26(56): 7731–7740PubMedCrossRefGoogle Scholar
  115. 115.
    Vasioukhin V, Degenstein L, Wise B, Fuchs E (1999) The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc Natl Acad Sci USA 96(15): 8551–8556PubMedCrossRefGoogle Scholar
  116. 116.
    Vogel H, Lim DS, Karsenty G, Finegold M, Hasty P (1999) Deletion of Ku86 causes early onset of senescence in mice. Proc Natl Acad Sci USA 96(19): 10770–10775PubMedCrossRefGoogle Scholar
  117. 117.
    Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8(4): 275–283PubMedCrossRefGoogle Scholar
  118. 118.
    Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2(8): 594–604PubMedCrossRefGoogle Scholar
  119. 119.
    Wagner KU, Wall RJ, St-Onge L, Gruss P, Wynshaw-Boris A, Garrett L, Li M, Furth PA, Hennighausen L (1997) Cre-mediated gene deletion in the mammary gland. Nucleic Acids Res 25(21): 4323–4330PubMedCrossRefGoogle Scholar
  120. 120.
    Wang Y, Putnam CD, Kane MF, Zhang W, Edelmann L, Russell R, Carrion DV, Chin L, Kucherlapati R, Kolodner RD, Edelmann W (2005) Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice. Nat Genet 37(7): 750–755PubMedCrossRefGoogle Scholar
  121. 121.
    Ward I, Chen J (2004) Early events in the DNA damage response. Curr Top Dev Biol 63: 1–35PubMedCrossRefGoogle Scholar
  122. 122.
    Ward IM, Minn K, van Deursen J, Chen J (2003) p53 Binding protein 53BP1 is required for DNA damage responses and tumor suppression in mice. Mol Cell Biol 23(7): 2556–2563PubMedCrossRefGoogle Scholar
  123. 123.
    Ward IM, Reina-San-Martin B, Olaru A, Minn K, Tamada K, Lau JS, Cascalho M, Chen L, Nussenzweig A, Livak F, Nussenzweig MC, Chen J (2004) 53BP1 is required for class switch recombination. J Cell Biol 165(4): 459–464PubMedCrossRefGoogle Scholar
  124. 124.
    Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, An P, Antonarakis SE, Attwood J, Baertsch R, Bailey J, Barlow K, Beck S, Berry E, Birren B, Bloom T, Bork P, Botcherby M, Bray N, Brent MR, Brown DG, Brown SD, Bult C, Burton J, Butler J, Campbell RD, Carninci P, Cawley S, Chiaromonte F, Chinwalla AT, Church DM, Clamp M, Clee C, Collins FS, Cook LL, Copley RR, Coulson A, Couronne O, Cuff J, Curwen V, Cutts T, Daly M, David R, Davies J, Delehaunty KD, Deri J, Dermitzakis ET, Dewey C, Dickens NJ, Diekhans M, Dodge S, Dubchak I, Dunn DM, Eddy SR, Elnitski L, Emes RD, Eswara P, Eyras E, Felsenfeld A, Fewell GA, Flicek P, Foley K, Frankel WN, Fulton LA, Fulton RS, Furey TS, Gage D, Gibbs RA, Glusman G, Gnerre S, Goldman N, Goodstadt L, Grafham D, Graves TA, Green ED, Gregory S, Guigo R, Guyer M, Hardison RC, Haussler D, Hayashizaki Y, Hillier LW, Hinrichs A, Hlavina W, Holzer T, Hsu F, Hua A, Hubbard T, Hunt A, Jackson I, Jaffe DB, Johnson LS, Jones M, Jones TA, Joy A, Kamal M, Karlsson EK, Karolchik D, Kasprzyk A, Kawai J, Keibler E, Kells C, Kent WJ, Kirby A, Kolbe DL, Korf I, Kucherlapati RS, Kulbokas EJ, Kulp D, Landers T, Leger JP, Leonard S, Letunic I, Levine R, Li J, Li M, Lloyd C, Lucas S, Ma B, Maglott DR, Mardis ER, Matthews L, Mauceli E, Mayer JH, McCarthy M, McCombie WR, McLaren S, McLay K, McPherson JD, Meldrim J, Meredith B, Mesirov JP, Miller W, Miner TL, Mongin E, Montgomery KT, Morgan M, Mott R, Mullikin JC, Muzny DM, Nash WE, Nelson JO, Nhan MN, Nicol R, Ning Z, Nusbaum C, O’Connor MJ, Okazaki Y, Oliver K, Overton-Larty E, Pachter L, Parra G, Pepin KH, Peterson J, Pevzner P, Plumb R, Pohl CS, Poliakov A, Ponce TC, Ponting CP, Potter S, Quail M, Reymond A, Roe BA, Roskin KM, Rubin EM, Rust AG, Santos R, Sapojnikov V, Schultz B, Schultz J, Schwartz MS, Schwartz S, Scott C, Seaman S, Searle S, Sharpe T, Sheridan A, Shownkeen R, Sims S, Singer JB, Slater G, Smit A, Smith DR, Spencer B, Stabenau A, Stange-Thomann N, Sugnet C, Suyama M, Tesler G, Thompson J, Torrents D, Trevaskis E, Tromp J, Ucla C, Ureta-Vidal A, Vinson JP, Von Niederhausern AC, Wade CM, Wall M, Weber RJ, Weiss RB, Wendl MC, West AP, Wetterstrand K, Wheeler R, Whelan S, Wierzbowski J, Willey D, Williams S, Wilson RK, Winter E, Worley KC, Wyman D, Yang S, Yang SP, Zdobnov EM, Zody MC, Lander ES (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420(6915): 520–562PubMedCrossRefGoogle Scholar
  125. 125.
    West SC (2003) Molecular views of recombination proteins and their control. Nat Rev Mol Cell Biol 4(6): 435–445PubMedCrossRefGoogle Scholar
  126. 126.
    Williams BR, Mirzoeva OK, Morgan WF, Lin J, Dunnick W, Petrini JH (2002) A murine model of Nijmegen breakage syndrome. Curr Biol 12(8): 648–653PubMedCrossRefGoogle Scholar
  127. 127.
    Wyman C, Kanaar R (2006) DNA double-strand break repair: all’s well that ends well. Annu Rev Genet 40: 363–383PubMedCrossRefGoogle Scholar
  128. 128.
    Xu X, Qiao W, Linke SP, Cao L, Li WM, Furth PA, Harris CC, Deng CX (2001) Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat Genet 28(3): 266–271PubMedCrossRefGoogle Scholar
  129. 129.
    Xu X, Wagner KU, Larson D, Weaver Z, Li C, Ried T, Hennighausen L, Wynshaw-Boris A, Deng CX (1999) Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat Genet 22(1): 37–43PubMedCrossRefGoogle Scholar
  130. 130.
    Xu Y, Ashley T, Brainerd EE, Bronson RT, Meyn MS, Baltimore D (1996) Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev 10(19): 2411–2422PubMedCrossRefGoogle Scholar
  131. 131.
    Yan CT, Kaushal D, Murphy M, Zhang Y, Datta A, Chen C, Monroe B, Mostoslavsky G, Coakley K, Gao Y, Mills KD, Fazeli AP, Tepsuporn S, Hall G, Mulligan R, Fox E, Bronson R, De Girolami U, Lee C, Alt FW (2006) XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice. Proc Natl Acad Sci USA 103(19): 7378–7383PubMedCrossRefGoogle Scholar
  132. 132.
    Zha S, Alt FW, Cheng HL, Brush JW, Li G (2007) Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficient murine ES cells. Proc Natl Acad Sci USA 104(11): 4518–4523PubMedCrossRefGoogle Scholar
  133. 133.
    Zha S, Sekiguchi J, Brush JW, Bassing CH, Alt FW (2008) Complementary functions of ATM and H2AX in development and suppression of genomic instability. Proc Natl Acad Sci USA 105(27): 9302–9306PubMedCrossRefGoogle Scholar
  134. 134.
    Zhu J, Petersen S, Tessarollo L, Nussenzweig A (2001) Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. Curr Biol 11(2): 105–109PubMedCrossRefGoogle Scholar
  135. 135.
    Zhuo L, Theis M, Alvarez-Maya I, Brenner M, Willecke K, Messing A (2001) hGFAP-Cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis 31(2): 85–94PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Department of Genetics and Tumor Cell BiologySt Jude Children’s Research HospitalMemphisUSA

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