Mechanisms of Recurrent Chromosomal Translocations

  • Richard L. Frock
  • Jiazhi Hu
  • Frederick W. AltEmail author


Chromosomal translocations frequently involve fusion of the ends of two separate DNA double-stranded breaks (DSBs) at distinct genomic locations. Recurrent chromosomal translocations are found in various cancers. Recently developed high-throughput approaches to clone genome-wide translocations that involve site-specific DSBs have provided new insights into mechanisms of chromosomal translocations. Such studies confirmed that, beyond cellular selection forces, basic mechanistic factors, including DSB frequency and persistence, as well as aspects of three dimensional genome organization, can contribute to recurrent translocations in a cell population. This review discusses our current view of the contribution of such mechanistic factors to recurrent chromosomal translocations.


Chromosomal translocations Genomic instability Lymphocyte development DNA breaks DNA repair 


  1. 1.
    Gainor JF, Shaw AT (2013) Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 18(7):865–875PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Kuppers R (2005) Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 5(4):251–262PubMedCrossRefGoogle Scholar
  3. 3.
    Mitelman F, Johansson B, Mertens F (2007) The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 7(4):233–245PubMedCrossRefGoogle Scholar
  4. 4.
    Nambiar M, Kari V, Raghavan SC (2008) Chromosomal translocations in cancer. Biochim Biophys Acta 1786(2):139–152PubMedGoogle Scholar
  5. 5.
    Alt FW et al (2013) Mechanisms of programmed DNA lesions and genomic instability in the immune system. Cell 152(3):417–429PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Groffen J et al (1984) Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36(1):93–99PubMedCrossRefGoogle Scholar
  7. 7.
    Lugo TG et al (1990) Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247(4946):1079–1082PubMedCrossRefGoogle Scholar
  8. 8.
    Nowell P, Hungerford D (1960) A minute chromosome in human chronic granulocytic leukemia [abstract]. Science 132:1497Google Scholar
  9. 9.
    Gostissa M, Alt FW, Chiarle R (2011) Mechanisms that promote and suppress chromosomal translocations in lymphocytes. Annu Rev Immunol 29:319–350PubMedCrossRefGoogle Scholar
  10. 10.
    Robbiani DF, Nussenzweig MC (2013) Chromosome translocation, B cell lymphoma, and activation-induced cytidine deaminase. Annu Rev Pathol 8:79–103PubMedCrossRefGoogle Scholar
  11. 11.
    Hnisz D et al (2013) Super-enhancers in the control of cell identity and disease. Cell 155(4):934–947PubMedCrossRefGoogle Scholar
  12. 12.
    Alt FW et al (1978) Selective multiplication of dihydrofolate reductase genes in methotrexate-resistant variants of cultured murine cells. J Biol Chem 253(5):1357–1370PubMedGoogle Scholar
  13. 13.
    Difilippantonio MJ et al (2002) Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification. J Exp Med 196(4):469–480PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Papenhausen PR, Griffin S, Tepperberg J (2005) Oncogene amplification in transforming myelodysplasia. Exp Mol Pathol 79(2):168–175PubMedCrossRefGoogle Scholar
  15. 15.
    Sharpless NE et al (2001) Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications, and deletions. Mol Cell 8(6):1187–1196PubMedCrossRefGoogle Scholar
  16. 16.
    Zhu C et al (2002) Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell 109(7):811–821PubMedCrossRefGoogle Scholar
  17. 17.
    McClintock B (1941) The stability of broken ends of chromosomes in Zea mays. Genetics 26(2):234–282PubMedCentralPubMedGoogle Scholar
  18. 18.
    Murnane JP (2012) Telomere dysfunction and chromosome instability. Mutat Res 730(1-2):28–36PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Albertson DG et al (2003) Chromosome aberrations in solid tumors. Nat Genet 34(4):369–376PubMedCrossRefGoogle Scholar
  20. 20.
    Rikova K et al (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131(6):1190–1203PubMedCrossRefGoogle Scholar
  21. 21.
    Albertson DG (2006) Gene amplification in cancer. Trends Genet 22(8):447–455PubMedCrossRefGoogle Scholar
  22. 22.
    Munshi NC, Avet-Loiseau H (2011) Genomics in multiple myeloma. Clin Cancer Res 17(6):1234–1242PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Zha S et al (2010) ATM-deficient thymic lymphoma is associated with aberrant tcrd rearrangement and gene amplification. J Exp Med 207(7):1369–1380PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Burkhardt L et al (2013) CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer. Cancer Res 73(9):2795–2805PubMedCrossRefGoogle Scholar
  25. 25.
    Gutierrez A et al (2011) The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia. Blood 118(15):4169–4173PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Krohn A et al (2014) Heterogeneity and chronology of PTEN deletion and ERG fusion in prostate cancer. Mod Pathol 27(12):1612–1620PubMedCrossRefGoogle Scholar
  27. 27.
    Larmonie NS et al (2013) Breakpoint sites disclose the role of the V(D)J recombination machinery in the formation of T-cell receptor (TCR) and non-TCR associated aberrations in T-cell acute lymphoblastic leukemia. Haematologica 98(8):1173–1184PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Gostissa M et al (2009) Chromosomal location targets different MYC family gene members for oncogenic translocations. Proc Natl Acad Sci U S A 106(7):2265–2270PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Wang JH et al (2009) Mechanisms promoting translocations in editing and switching peripheral B cells. Nature 460(7252):231–236PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Deriano L, Roth DB (2013) Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage. Annu Rev Genet 47:433–455PubMedCrossRefGoogle Scholar
  31. 31.
    Shiloh Y, Ziv Y (2013) The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 14(4):197–210CrossRefGoogle Scholar
  32. 32.
    Zhang Y et al (2010) The role of mechanistic factors in promoting chromosomal translocations found in lymphoid and other cancers. Adv Immunol 106:93–133PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Symington LS, Gautier J (2011) Double-strand break end resection and repair pathway choice. Annu Rev Genet 45:247–271PubMedCrossRefGoogle Scholar
  34. 34.
    Chapman JR, Taylor MR, Boulton SJ (2012) Playing the end game: DNA double-strand break repair pathway choice. Mol Cell 47(4):497–510PubMedCrossRefGoogle Scholar
  35. 35.
    Boboila C, Alt FW, Schwer B (2012) Classical and alternative end-joining pathways for repair of lymphocyte-specific and general DNA double-strand breaks. Adv Immunol 116:1–49PubMedCrossRefGoogle Scholar
  36. 36.
    Kim N, Jinks-Robertson S (2012) Transcription as a source of genome instability. Nat Rev Genet 13(3):204–214PubMedCentralPubMedGoogle Scholar
  37. 37.
    Lieberman-Aiden E et al (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326(5950):289–293PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Zhang Y et al (2012) Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell 148(5):908–921PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Gostissa M et al (2014) IgH class switching exploits a general property of two DNA breaks to be joined in cis over long chromosomal distances. Proc Natl Acad Sci U S A 111(7):2644–2649PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Lucas JS et al (2014) 3D trajectories adopted by coding and regulatory DNA elements: first-passage times for genomic interactions. Cell 158(2):339–352PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Dion V, Gasser SM (2013) Chromatin movement in the maintenance of genome stability. Cell 152(6):1355–1364PubMedCrossRefGoogle Scholar
  42. 42.
    Mine-Hattab J, Rothstein R (2012) Increased chromosome mobility facilitates homology search during recombination. Nat Cell Biol 14(5):510–517PubMedCrossRefGoogle Scholar
  43. 43.
    Dimitrova N et al (2008) 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility. Nature 456(7221):524–528PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Roukos V et al (2013) Spatial dynamics of chromosome translocations in living cells. Science 341(6146):660–664PubMedCrossRefGoogle Scholar
  45. 45.
    Chiarle R et al (2011) Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell 147(1):107–119PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Klein IA et al (2011) Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell 147(1):95–106PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Haber JE (2006) Transpositions and translocations induced by site-specific double-strand breaks in budding yeast. DNA Repair (Amst) 5(9–10):998–1009CrossRefGoogle Scholar
  48. 48.
    Zarrin AA et al (2007) Antibody class switching mediated by yeast endonuclease-generated DNA breaks. Science 315(5810):377–381PubMedCrossRefGoogle Scholar
  49. 49.
    Hu J et al (2014) Developmental propagation of V(D)J recombination-associated DNA breaks and translocations in mature B cells via dicentric chromosomes. Proc Natl Acad Sci U S A 111(28):10269–10274PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Kim YG, Cha J, Chandrasegaran S (1996) Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc Natl Acad Sci U S A 93(3):1156–1160PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Christian M et al (2010) Targeting DNA double-strand breaks with TAL effector nucleases. Genetics 186(2):757–761PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Jinek M et al (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337(6096):816–821PubMedCrossRefGoogle Scholar
  53. 53.
    Brunet E et al (2009) Chromosomal translocations induced at specified loci in human stem cells. Proc Natl Acad Sci U S A 106(26):10620–10625PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Piganeau M et al (2013) Cancer translocations in human cells induced by zinc finger and TALE nucleases. Genome Res 23(7):1182–1193PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Frock RL et al (2015) Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. Nat Biotechnol 33(2):179–86Google Scholar
  56. 56.
    Vilenchik MM, Knudson AG (2003) Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci U S A 100(22):12871–12876PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    De Bont R, van Larebeke N (2004) Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis 19(3):169–185PubMedCrossRefGoogle Scholar
  58. 58.
    Aguilera A, Garcia-Muse T (2013) Causes of genome instability. Annu Rev Genet 47:1–32PubMedCrossRefGoogle Scholar
  59. 59.
    Branzei D, Foiani M (2010) Maintaining genome stability at the replication fork. Nat Rev Mol Cell Biol 11(3):208–219PubMedCrossRefGoogle Scholar
  60. 60.
    Hu J et al (2012) The intra-S phase checkpoint targets Dna2 to prevent stalled replication forks from reversing. Cell 149(6):1221–1232PubMedCrossRefGoogle Scholar
  61. 61.
    Lambert S, Carr AM (2013) Impediments to replication fork movement: stabilisation, reactivation and genome instability. Chromosoma 122(1–2):33–45PubMedCrossRefGoogle Scholar
  62. 62.
    Ferber MJ et al (2004) Positioning of cervical carcinoma and Burkitt lymphoma translocation breakpoints with respect to the human papillomavirus integration cluster in FRA8C at 8q24.13. Cancer Genet Cytogenet 154(1):1–9PubMedCrossRefGoogle Scholar
  63. 63.
    Morelli C et al (2002) Cloning and characterization of the common fragile site FRA6F harboring a replicative senescence gene and frequently deleted in human tumors. Oncogene 21(47):7266–7276PubMedCrossRefGoogle Scholar
  64. 64.
    Sinclair PB et al (2004) A fluorescence in situ hybridization map of 6q deletions in acute lymphocytic leukemia: identification and analysis of a candidate tumor suppressor gene. Cancer Res 64(12):4089–4098PubMedCrossRefGoogle Scholar
  65. 65.
    Barlow JH et al (2013) Identification of early replicating fragile sites that contribute to genome instability. Cell 152(3):620–632PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Fong YW, Cattoglio C, Tjian R (2013) The intertwined roles of transcription and repair proteins. Mol Cell 52(3):291–302PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Helmrich A, Ballarino M, Tora L (2011) Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol Cell 44(6):966–977PubMedCrossRefGoogle Scholar
  68. 68.
    Prado F, Aguilera A (2005) Impairment of replication fork progression mediates RNA polII transcription-associated recombination. EMBO J 24(6):1267–1276PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Haffner MC et al (2011) Transcription-induced DNA double strand breaks: both oncogenic force and potential therapeutic target? Clin Cancer Res 17(12):3858–3864PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Li X, Manley JL (2005) Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 122(3):365–378PubMedCrossRefGoogle Scholar
  71. 71.
    Shinkura R et al (2003) The influence of transcriptional orientation on endogenous switch region function. Nat Immunol 4(5):435–441PubMedCrossRefGoogle Scholar
  72. 72.
    Yu K et al (2003) R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells. Nat Immunol 4(5):442–451PubMedCrossRefGoogle Scholar
  73. 73.
    Curtin NJ (2012) DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 12(12):801–817PubMedCrossRefGoogle Scholar
  74. 74.
    Mehta A, Haber JE (2014) Sources of DNA double-strand breaks and models of recombinational DNA repair. Cold Spring Harb Perspect Biol 6(9):a016428PubMedCrossRefGoogle Scholar
  75. 75.
    Asaithamby A, Chen DJ (2009) Cellular responses to DNA double-strand breaks after low-dose gamma-irradiation. Nucleic Acids Res 37(12):3912–3923PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Joannides M, Grimwade D (2010) Molecular biology of therapy-related leukaemias. Clin Transl Oncol 12(1):8–14PubMedCrossRefGoogle Scholar
  77. 77.
    Joannides M et al (2011) Molecular pathogenesis of secondary acute promyelocytic leukemia. Mediterr J Hematol Infect Dis 3(1), e2011045PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Helmink BA, Sleckman BP (2012) The response to and repair of RAG-mediated DNA double-strand breaks. Annu Rev Immunol 30:175–202PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Janz S (2006) Myc translocations in B cell and plasma cell neoplasms. DNA Repair (Amst) 5(9–10):1213–1224CrossRefGoogle Scholar
  80. 80.
    Krangel MS (2009) Mechanics of T cell receptor gene rearrangement. Curr Opin Immunol 21(2):133–139PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Nishana M, Raghavan SC (2012) Role of recombination activating genes in the generation of antigen receptor diversity and beyond. Immunology 137(4):271–281PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Schatz DG, Baltimore D (2004) Uncovering the V(D)J recombinase. Cell 116(2 Suppl):S103–S106, 2 p following S106PubMedCrossRefGoogle Scholar
  83. 83.
    Fugmann SD et al (2000) The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu Rev Immunol 18:495–527PubMedCrossRefGoogle Scholar
  84. 84.
    Schatz DG, Swanson PC (2011) V(D)J recombination: mechanisms of initiation. Annu Rev Genet 45:167–202PubMedCrossRefGoogle Scholar
  85. 85.
    Bossen C, Mansson R, Murre C (2012) Chromatin topology and the regulation of antigen receptor assembly. Annu Rev Immunol 30:337–356PubMedCrossRefGoogle Scholar
  86. 86.
    Hewitt SL, Chaumeil J, Skok JA (2010) Chromosome dynamics and the regulation of V(D)J recombination. Immunol Rev 237(1):43–54PubMedCrossRefGoogle Scholar
  87. 87.
    Desiderio S (2010) Temporal and spatial regulatory functions of the V(D)J recombinase. Semin Immunol 22(6):362–369PubMedCrossRefGoogle Scholar
  88. 88.
    Ji Y et al (2010) The in vivo pattern of binding of RAG1 and RAG2 to antigen receptor loci. Cell 141(3):419–431PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Matthews AG, Oettinger MA (2009) RAG: a recombinase diversified. Nat Immunol 10(8):817–821PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Schatz DG, Ji Y (2011) Recombination centres and the orchestration of V(D)J recombination. Nat Rev Immunol 11(4):251–263PubMedCrossRefGoogle Scholar
  91. 91.
    Taccioli GE et al (1993) Impairment of V(D)J recombination in double-strand break repair mutants. Science 260(5105):207–210PubMedCrossRefGoogle Scholar
  92. 92.
    Alt FW, Baltimore D (1982) Joining of immunoglobulin heavy chain gene segments: implications from a chromosome with evidence of three D-JH fusions. Proc Natl Acad Sci U S A 79(13):4118–4122PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Chaudhuri J et al (2007) Evolution of the immunoglobulin heavy chain class switch recombination mechanism. Adv Immunol 94:157–214PubMedCrossRefGoogle Scholar
  94. 94.
    Honjo T, Kinoshita K, Muramatsu M (2002) Molecular mechanism of class switch recombination: linkage with somatic hypermutation. Annu Rev Immunol 20:165–196PubMedCrossRefGoogle Scholar
  95. 95.
    Jung D et al (2006) Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu Rev Immunol 24:541–570PubMedCrossRefGoogle Scholar
  96. 96.
    Muramatsu M et al (2000) Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102(5):553–563PubMedCrossRefGoogle Scholar
  97. 97.
    Peled JU et al (2008) The biochemistry of somatic hypermutation. Annu Rev Immunol 26:481–511PubMedCrossRefGoogle Scholar
  98. 98.
    Rogozin IB, Diaz M (2004) Cutting edge: DGYW/WRCH is a better predictor of mutability at G:C bases in Ig hypermutation than the widely accepted RGYW/WRCY motif and probably reflects a two-step activation-induced cytidine deaminase-triggered process. J Immunol 172(6):3382–3384PubMedCrossRefGoogle Scholar
  99. 99.
    Hackney JA et al (2009) DNA targets of AID evolutionary link between antibody somatic hypermutation and class switch recombination. Adv Immunol 101:163–189PubMedCrossRefGoogle Scholar
  100. 100.
    Storb U (2014) Why does somatic hypermutation by AID require transcription of its target genes? Adv Immunol 122:253–277PubMedCrossRefGoogle Scholar
  101. 101.
    Di Noia JM, Neuberger MS (2007) Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem 76:1–22PubMedCrossRefGoogle Scholar
  102. 102.
    Stavnezer J, Guikema JE, Schrader CE (2008) Mechanism and regulation of class switch recombination. Annu Rev Immunol 26:261–292PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Daniel JA, Nussenzweig A (2013) The AID-induced DNA damage response in chromatin. Mol Cell 50(3):309–321PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Keim C et al (2013) Regulation of AID, the B-cell genome mutator. Genes Dev 27(1):1–17PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Matthews AJ et al (2014) Regulation of immunoglobulin class-switch recombination: choreography of noncoding transcription, targeted DNA deamination, and long-range DNA repair. Adv Immunol 122:1–57PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Wuerffel R et al (2007) S-S synapsis during class switch recombination is promoted by distantly located transcriptional elements and activation-induced deaminase. Immunity 27(5):711–722PubMedCrossRefGoogle Scholar
  107. 107.
    Bednarski JJ, Sleckman BP (2012) Lymphocyte development: integration of DNA damage response signaling. Adv Immunol 116:175–204PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Chaumeil J et al (2013) Higher-order looping and nuclear organization of Tcra facilitate targeted rag cleavage and regulated rearrangement in recombination centers. Cell Rep 3(2):359–370PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Deriano L et al (2011) The RAG2 C terminus suppresses genomic instability and lymphomagenesis. Nature 471(7336):119–123PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Dyer MJ et al (2010) Immunoglobulin heavy chain locus chromosomal translocations in B-cell precursor acute lymphoblastic leukemia: rare clinical curios or potent genetic drivers? Blood 115(8):1490–1499PubMedCrossRefGoogle Scholar
  111. 111.
    Tepsuporn S et al (2014) Mechanisms that can promote peripheral B-cell lymphoma in ATM-deficient mice. Cancer Immunol Res 2(9):857–866PubMedCentralPubMedCrossRefGoogle Scholar
  112. 112.
    Wesemann DR et al (2013) Microbial colonization influences early B-lineage development in the gut lamina propria. Nature 501(7465):112–115PubMedCrossRefGoogle Scholar
  113. 113.
    Merelli I et al (2010) RSSsite: a reference database and prediction tool for the identification of cryptic recombination signal sequences in human and murine genomes. Nucleic Acids Res 38(Web Server issue):W262–W267PubMedCentralPubMedCrossRefGoogle Scholar
  114. 114.
    Tsai AG, Lieber MR (2010) Mechanisms of chromosomal rearrangement in the human genome. BMC Genomics 11(Suppl 1):S1PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Mendes RD et al (2014) PTEN microdeletions in T-cell acute lymphoblastic leukemia are caused by illegitimate RAG-mediated recombination events. Blood 124(4):567–578PubMedCrossRefGoogle Scholar
  116. 116.
    Pasqualucci L et al (2001) Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412(6844):341–346PubMedCrossRefGoogle Scholar
  117. 117.
    Liu M et al (2008) Two levels of protection for the B cell genome during somatic hypermutation. Nature 451(7180):841–845PubMedCrossRefGoogle Scholar
  118. 118.
    Hakim O et al (2012) DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes. Nature 484(7392):69–74PubMedCentralPubMedGoogle Scholar
  119. 119.
    Pavri R, Nussenzweig MC (2011) AID targeting in antibody diversity. Adv Immunol 110:1–26PubMedCrossRefGoogle Scholar
  120. 120.
    Liu M, Schatz DG (2009) Balancing AID and DNA repair during somatic hypermutation. Trends Immunol 30(4):173–181PubMedCrossRefGoogle Scholar
  121. 121.
    Pasqualucci L et al (2008) AID is required for germinal center-derived lymphomagenesis. Nat Genet 40(1):108–112PubMedCrossRefGoogle Scholar
  122. 122.
    Meng F-L et al (2014) Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell 159(7):1538–1548Google Scholar
  123. 123.
    Lieber MR (2010) The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem 79:181–211PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Sun J et al (2012) Human Ku70/80 protein blocks exonuclease 1-mediated DNA resection in the presence of human Mre11 or Mre11/Rad50 protein complex. J Biol Chem 287(7):4936–4945PubMedCentralPubMedCrossRefGoogle Scholar
  125. 125.
    Kumar V, Alt FW, Oksenych V (2014) Functional overlaps between XLF and the ATM-dependent DNA double strand break response. DNA Repair (Amst) 16:11–22CrossRefGoogle Scholar
  126. 126.
    Buck D et al (2006) Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124(2):287–299PubMedCrossRefGoogle Scholar
  127. 127.
    Du L et al (2012) Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis. J Exp Med 209(2):291–305PubMedCentralPubMedCrossRefGoogle Scholar
  128. 128.
    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
  129. 129.
    Lu H et al (2007) Length-dependent binding of human XLF to DNA and stimulation of XRCC4.DNA ligase IV activity. J Biol Chem 282(15):11155–11162PubMedCrossRefGoogle Scholar
  130. 130.
    Mahaney BL et al (2013) XRCC4 and XLF form long helical protein filaments suitable for DNA end protection and alignment to facilitate DNA double strand break repair. Biochem Cell Biol 91(1):31–41PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    Tsai CJ, Kim SA, Chu G (2007) Cernunnos/XLF promotes the ligation of mismatched and noncohesive DNA ends. Proc Natl Acad Sci U S A 104(19):7851–7856PubMedCentralPubMedCrossRefGoogle Scholar
  132. 132.
    de Villartay JP (2009) V(D)J recombination deficiencies. Adv Exp Med Biol 650:46–58PubMedCrossRefGoogle Scholar
  133. 133.
    van der Burg M et al (2009) A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. J Clin Invest 119(1):91–98PubMedCentralPubMedGoogle Scholar
  134. 134.
    Frank KM et al (1998) Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 396(6707):173–177PubMedCrossRefGoogle Scholar
  135. 135.
    Gao Y et al (1998) A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95(7):891–902PubMedCrossRefGoogle Scholar
  136. 136.
    Gu Y et al (2000) Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit-deficient mice. Proc Natl Acad Sci U S A 97(6):2668–2673PubMedCentralPubMedCrossRefGoogle Scholar
  137. 137.
    Frank KM et al (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
  138. 138.
    Gao Y et al (2000) Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 404(6780):897–900PubMedCrossRefGoogle Scholar
  139. 139.
    Rooney S, Chaudhuri J, Alt FW (2004) The role of the non-homologous end-joining pathway in lymphocyte development. Immunol Rev 200(1):115–131PubMedCrossRefGoogle Scholar
  140. 140.
    Frappart PO et al (2009) Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency. Proc Natl Acad Sci U S A 106(6):1880–1885PubMedCentralPubMedCrossRefGoogle Scholar
  141. 141.
    Yan CT et al (2006) XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice. Proc Natl Acad Sci U S A 103(19):7378–7383PubMedCentralPubMedCrossRefGoogle Scholar
  142. 142.
    Li G et al (2008) Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V(D)J recombination. Mol Cell 31(5):631–640PubMedCentralPubMedCrossRefGoogle Scholar
  143. 143.
    Boboila C et al (2010) Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70. Proc Natl Acad Sci U S A 107(7):3034–3039PubMedCentralPubMedCrossRefGoogle Scholar
  144. 144.
    Ferguson DO et al (2000) The interplay between nonhomologous end-joining and cell cycle checkpoint factors in development, genomic stability, and tumorigenesis. Cold Spring Harb Symp Quant Biol 65:395–403PubMedCrossRefGoogle Scholar
  145. 145.
    Wang JH et al (2008) Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching. J Exp Med 205(13):3079–3090PubMedCentralPubMedCrossRefGoogle Scholar
  146. 146.
    Boulton SJ, Jackson SP (1996) Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double-strand break repair and serves as a barrier to error-prone DNA repair pathways. EMBO J 15(18):5093–5103PubMedCentralPubMedGoogle Scholar
  147. 147.
    Kabotyanski EB et al (1998) Double-strand break repair in Ku86- and XRCC4-deficient cells. Nucleic Acids Res 26(23):5333–5342PubMedCentralPubMedCrossRefGoogle Scholar
  148. 148.
    Boboila C et al (2010) Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4. J Exp Med 207(2):417–427PubMedCentralPubMedCrossRefGoogle Scholar
  149. 149.
    Yan CT et al (2007) IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449(7161):478–482PubMedCrossRefGoogle Scholar
  150. 150.
    Stephens PJ et al (2009) Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462(7276):1005–1010PubMedCentralPubMedCrossRefGoogle Scholar
  151. 151.
    Zhang Y, Rowley JD (2006) Chromatin structural elements and chromosomal translocations in leukemia. DNA Repair (Amst) 5(9–10):1282–1297CrossRefGoogle Scholar
  152. 152.
    Grabarz A et al (2012) Initiation of DNA double strand break repair: signaling and single-stranded resection dictate the choice between homologous recombination, non-homologous end-joining and alternative end-joining. Am J Cancer Res 2(3):249–268PubMedCentralPubMedGoogle Scholar
  153. 153.
    Guirouilh-Barbat J et al (2007) Defects in XRCC4 and KU80 differentially affect the joining of distal nonhomologous ends. Proc Natl Acad Sci U S A 104(52):20902–20907PubMedCentralPubMedCrossRefGoogle Scholar
  154. 154.
    Komori T, Sugiyama H (1993) N sequences, P nucleotides and short sequence homologies at junctional sites in VH to VHDJH and VHDJH to JH joining. Mol Immunol 30(16):1393–1398PubMedCrossRefGoogle Scholar
  155. 155.
    Stavnezer J et al (2010) Mapping of switch recombination junctions, a tool for studying DNA repair pathways during immunoglobulin class switching. Adv Immunol 108:45–109PubMedCrossRefGoogle Scholar
  156. 156.
    Simsek D, Jasin M (2010) Alternative end-joining is suppressed by the canonical NHEJ component Xrcc4-ligase IV during chromosomal translocation formation. Nat Struct Mol Biol 17(4):410–416PubMedCentralPubMedCrossRefGoogle Scholar
  157. 157.
    Ghezraoui H et al (2014) Chromosomal translocations in human cells are generated by canonical nonhomologous end-joining. Mol Cell 55(6):829–842PubMedCentralPubMedCrossRefGoogle Scholar
  158. 158.
    Perlman S, Becker-Catania S, Gatti RA (2003) Ataxia-telangiectasia: diagnosis and treatment. Semin Pediatr Neurol 10(3):173–182PubMedCrossRefGoogle Scholar
  159. 159.
    Choi M et al (2012) Attractor landscape analysis reveals feedback loops in the p53 network that control the cellular response to DNA damage. Sci Signal 5(251):ra83PubMedCrossRefGoogle Scholar
  160. 160.
    Nussenzweig A, Nussenzweig MC (2010) Origin of chromosomal translocations in lymphoid cancer. Cell 141(1):27–38PubMedCentralPubMedCrossRefGoogle Scholar
  161. 161.
    Scully R, Xie A (2013) Double strand break repair functions of histone H2AX. Mutat Res 750(1–2):5–14PubMedCrossRefGoogle Scholar
  162. 162.
    Al-Hakim A et al (2010) The ubiquitous role of ubiquitin in the DNA damage response. DNA Repair (Amst) 9(12):1229–1240CrossRefGoogle Scholar
  163. 163.
    Panier S, Boulton SJ (2014) Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Biol 15(1):7–18PubMedCrossRefGoogle Scholar
  164. 164.
    Sirbu BM, Cortez D (2013) DNA damage response: three levels of DNA repair regulation. Cold Spring Harb Perspect Biol 5(8):a012724PubMedCentralPubMedCrossRefGoogle Scholar
  165. 165.
    Zimmermann M, de Lange T (2014) 53BP1: pro choice in DNA repair. Trends Cell Biol 24(2):108–117PubMedCentralPubMedCrossRefGoogle Scholar
  166. 166.
    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
  167. 167.
    Franco S, Alt FW, Manis JP (2006) Pathways that suppress programmed DNA breaks from progressing to chromosomal breaks and translocations. DNA Repair (Amst) 5(9-10):1030–1041CrossRefGoogle Scholar
  168. 168.
    Lavin MF (2008) Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 9(10):759–769PubMedCrossRefGoogle Scholar
  169. 169.
    Xu Y et al (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
  170. 170.
    Bassing CH et al (2002) Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX. Proc Natl Acad Sci U S A 99(12):8173–8178PubMedCentralPubMedCrossRefGoogle Scholar
  171. 171.
    Franco S et al (2006) H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol Cell 21(2):201–214PubMedCrossRefGoogle Scholar
  172. 172.
    Bassing CH et al (2003) Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114(3):359–370PubMedCrossRefGoogle Scholar
  173. 173.
    Celeste A et al (2003) H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114(3):371–383PubMedCrossRefGoogle Scholar
  174. 174.
    Ramiro AR et al (2006) Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature 440(7080):105–109PubMedCentralPubMedCrossRefGoogle Scholar
  175. 175.
    Manis JP et al (2004) 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat Immunol 5(5):481–487PubMedCrossRefGoogle Scholar
  176. 176.
    Ward IM et al (2004) 53BP1 is required for class switch recombination. J Cell Biol 165(4):459–464PubMedCentralPubMedCrossRefGoogle Scholar
  177. 177.
    Celeste A et al (2002) Genomic instability in mice lacking histone H2AX. Science 296(5569):922–927PubMedCrossRefGoogle Scholar
  178. 178.
    Zha S et al (2011) ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks. Nature 469(7329):250–254PubMedCentralPubMedCrossRefGoogle Scholar
  179. 179.
    Liu X et al (2012) Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development. Proc Natl Acad Sci U S A 109(10):3903–3908PubMedCentralPubMedCrossRefGoogle Scholar
  180. 180.
    Oksenych V et al (2012) Functional redundancy between repair factor XLF and damage response mediator 53BP1 in V(D)J recombination and DNA repair. Proc Natl Acad Sci U S A 109(7):2455–2460PubMedCentralPubMedCrossRefGoogle Scholar
  181. 181.
    Gumy-Pause F, Wacker P, Sappino AP (2004) ATM gene and lymphoid malignancies. Leukemia 18(2):238–242PubMedCrossRefGoogle Scholar
  182. 182.
    McKinnon PJ (2012) ATM and the molecular pathogenesis of ataxia telangiectasia. Annu Rev Pathol 7:303–321PubMedCrossRefGoogle Scholar
  183. 183.
    Callen E et al (2007) ATM prevents the persistence and propagation of chromosome breaks in lymphocytes. Cell 130(1):63–75PubMedCrossRefGoogle Scholar
  184. 184.
    Roix JJ et al (2003) Spatial proximity of translocation-prone gene loci in human lymphomas. Nat Genet 34(3):287–291PubMedCrossRefGoogle Scholar
  185. 185.
    Dixon JR et al (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485(7398):376–380PubMedCentralPubMedCrossRefGoogle Scholar
  186. 186.
    Nagano T et al (2013) Single-cell Hi-C reveals cell-to-cell variability in chromosome structure. Nature 502(7469):59–64PubMedCrossRefGoogle Scholar
  187. 187.
    Dekker J, Marti-Renom MA, Mirny LA (2013) Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat Rev Genet 14(6):390–403PubMedCentralPubMedCrossRefGoogle Scholar
  188. 188.
    Gibcus JH, Dekker J (2013) The hierarchy of the 3D genome. Mol Cell 49(5):773–782PubMedCentralPubMedCrossRefGoogle Scholar
  189. 189.
    Dion V et al (2012) Increased mobility of double-strand breaks requires Mec1, Rad9 and the homologous recombination machinery. Nat Cell Biol 14(5):502–509PubMedCrossRefGoogle Scholar
  190. 190.
    Onozawa M, Aplan PD (2012) Illegitimate V(D)J recombination involving nonantigen receptor loci in lymphoid malignancy. Genes Chromosom Cancer 51(6):525–535PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Richard L. Frock
    • 1
  • Jiazhi Hu
    • 1
  • Frederick W. Alt
    • 1
    Email author
  1. 1.Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children’s Hospital, and Department of GeneticsHarvard Medical SchoolBostonUSA

Personalised recommendations