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End-joining, translocations and cancer

Key Points

  • Translocations that create neomorphic fusion genes occur in both lymphoid malignancies and solid tumours.

  • A large number of translocations do not encode fusion genes and may not contribute to malignancy.

  • Translocations frequently contain complex, clustered sequence rearrangements, similar to chromothrypsis, and may also contain genetic material from several different chromosomes.

  • Many translocations arise as a consequence of 'classical' or 'alternative' pathways of non-homologous end-joining.

  • Mammalian cells have regulatory systems to bias DNA repair towards repair pathways that are less likely to contribute to translocation.

  • Frequency of DNA breakage is the metric that best predicts the likelihood of a particular genomic site being involved in a translocation.

  • Therapeutic intervention to reduce translocation frequency is a potential mechanism for reducing the risk of cancer.

Abstract

Fusion genes that are caused by chromosome translocations have been recognized for several decades as drivers of deregulated cell growth in certain types of cancer. In recent years, oncogenic fusion genes have been found in many haematological and solid tumours, demonstrating that translocations are a common cause of malignancy. Sequencing approaches have now confirmed that numerous, non-clonal translocations are a typical feature of cancer cells. These chromosome rearrangements are often highly complex and contain DNA sequence from multiple genomic sites. The factors and pathways that promote translocations are becoming clearer, with non-homologous end-joining implicated as a key source of genomic rearrangements.

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Figure 1: Visualizing translocations.
Figure 2: Pathways to translocation.
Figure 3: Oncogene amplification by breakage–fusion–bridge cycles.
Figure 4: Steps in classical and alternative end-joining.
Figure 5: Regulation of DNA double-strand break repair pathways.

References

  1. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Forment, J. V., Kaidi, A. & Jackson, S. P. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nature Rev. Cancer 12, 663–670 (2012).

    Article  CAS  Google Scholar 

  3. Giardino, D. et al. De novo balanced chromosome rearrangements in prenatal diagnosis. Prenat Diagn. 29, 257–265 (2009).

    Google Scholar 

  4. Warburton, D. De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am. J. Hum. Genet. 49, 995–1013 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Hakim, O. et al. DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes. Nature 484, 69–74 (2012). Translocation is most closely linked to frequency of DNA breakage, but also correlates with transcription. This article extended these observations and showed that nuclear architecture is a relatively weak predictor of translocation frequency.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Klein, I. A. et al. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell 147, 95–106 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chiarle, R. et al. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell 147, 107–119 (2011). References 6 and 7 showed a strong proximity effect for joining of DNA breaks, with intrachromosomal joining being preferred.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kato, L. et al. Nonimmunoglobulin target loci of activation-induced cytidine deaminase (AID) share unique features with immunoglobulin genes. Proc. Natl Acad. Sci. USA 109, 2479–2484 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Mitelman, F., Johansson, B. & Mertens, F. The impact of translocations and gene fusions on cancer causation. Nature Rev. Cancer 7, 233–245 (2007).

    Article  CAS  Google Scholar 

  10. Rabbitts, T. H. Commonality but diversity in cancer gene fusions. Cell 137, 391–395 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012). One of a series of reports from The Cancer Genome Atlas consortium. This study revealed frequently mutated cancer genes and a pattern of recurrent and sporadic translocations and chromosome rearrangements.

  13. Stephens, P. J. et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005–1010 (2009). This paper, one of several recent publications from Michael Stratton's group exploring the genomic landscape of breast cancer, revealed new fusion genes formed by translocations in breast cancer cells and also demonstrated the frequency and complexity of breast cancer translocations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang, J. et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Berger, M. F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cancer Genome Atlas Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012).

  17. Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Krzywinski, M. et al. Circos: an information aesthetic for comparative genomics. Genome Res. 19, 1639–1645 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Maher, C. A. & Wilson, R. K. Chromothripsis and human disease: piecing together the shattering process. Cell 148, 29–32 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Berger, M. F. et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature 485, 502–506 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hastings, P. J., Lupski, J. R., Rosenberg, S. M. & Ira, G. Mechanisms of change in gene copy number. Nature Rev. Genet. 10, 551–564 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Llorente, B., Smith, C. E. & Symington, L. S. Break-induced replication: what is it and what is it for? Cell Cycle 7, 859–864 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Ruiz, J. F., Gomez-Gonzalez, B. & Aguilera, A. Chromosomal translocations caused by either pol32-dependent or pol32-independent triparental break-induced replication. Mol. Cell. Biol. 29, 5441–5454 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Smith, C. E., Llorente, B. & Symington, L. S. Template switching during break-induced replication. Nature 447, 102–105 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Shaw, C. J. & Lupski, J. R. Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum. Mol. Genet. 13, R57–R64 (2004). This report provides evidence that, in Saccharomyces cerevisiae , chromosome rearrangements can occur by a process involving break-induced repair with multiple rounds of strand invasion.

    Article  CAS  PubMed  Google Scholar 

  27. Lieber, M. R. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu. Rev. Biochem. 79, 181–211 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Difilippantonio, M. J. et al. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 404, 510–514 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ferguson, D. O. et al. The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations. Proc. Natl Acad. Sci. USA 97, 6630–6633 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gao, Y. et al. Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 404, 897–900 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Saberi, A. et al. RAD18 and poly(ADP-ribose) polymerase independently suppress the access of nonhomologous end joining to double-strand breaks and facilitate homologous recombination-mediated repair. Mol. Cell. Biol. 27, 2562–2571 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Adamo, A. et al. Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. Mol. Cell 39, 25–35 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Bunting, S. F. et al. BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. Mol. Cell 46, 125–135 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010). This paper demonstrated that 53BP1 represses the use of the error-free homologous recombination pathway for the repair of DNA double-strand breaks and increases the use of a mutational mechanism involving NHEJ that causes cancer in BRCA1-deficient mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pace, P. et al. Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway. Science 329, 219–223 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Patel, A. G., Sarkaria, J. N. & Kaufmann, S. H. Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc. Natl Acad. Sci. USA 108, 3406–3411 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Cancer Genome Atlas Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011). A study from The Cancer Genome Atlas consortium suggesting that up to 50% of ovarian carcinoma cases involve mutations that inactivatethe homologous recombination pathway for DNA repair.

  38. Park, D. J. et al. Rare mutations in XRCC2 increase the risk of breast cancer. Am. J. Hum. Genet. 90, 734–739 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Stephens, P. J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400–404 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Thompson, E. R. et al. Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet. 8, e1002894 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Roth, D. B., Porter, T. N. & Wilson, J. H. Mechanisms of nonhomologous recombination in mammalian cells. Mol. Cell. Biol. 5, 2599–2607 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Roth, D. B. & Wilson, J. H. Nonhomologous recombination in mammalian cells: role for short sequence homologies in the joining reaction. Mol. Cell. Biol. 6, 4295–4304 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Boulton, S. J. & Jackson, S. P. Identification of a Saccharomyces cerevisiae Ku80 homologue: roles in DNA double strand break rejoining and in telomeric maintenance. Nucleic Acids Res. 24, 4639–4648 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Boulton, S. J. & Jackson, S. P. Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double-strand break repair and serves as a barrier to error-prone DNA repair pathways. EMBO J. 15, 5093–5103 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kramer, K. M., Brock, J. A., Bloom, K., Moore, J. K. & Haber, J. E. Two different types of double-strand breaks in Saccharomyces cerevisiae are repaired by similar RAD52-independent, nonhomologous recombination events. Mol. Cell. Biol. 14, 1293–1301 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wang, H. et al. Biochemical evidence for Ku-independent backup pathways of NHEJ. Nucleic Acids Res. 31, 5377–5388 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Daley, J. M. & Wilson, T. E. Rejoining of DNA double-strand breaks as a function of overhang length. Mol. Cell. Biol. 25, 896–906 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Difilippantonio, M. J. et al. Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification. J. Exp. Med. 196, 469–480 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhu, C. et al. Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell 109, 811–821 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Weinstock, D. M., Elliott, B. & Jasin, M. A model of oncogenic rearrangements: differences between chromosomal translocation mechanisms and simple double-strand break repair. Blood 107, 777–780 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Boboila, C. et al. Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4. J. Exp. Med. 207, 417–427 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Simsek, D. & Jasin, M. Alternative end-joining is suppressed by the canonical NHEJ component Xrcc4-ligase IV during chromosomal translocation formation. Nature Struct. Mol. Biol. 17, 410–416 (2010).

    Article  CAS  Google Scholar 

  53. McVey, M. & Lee, S. E. MMEJ repair of double-strand breaks (director's cut): deleted sequences and alternative endings. Trends Genet. 24, 529–538 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tsai, A. G. et al. Human chromosomal translocations at CpG sites and a theoretical basis for their lineage and stage specificity. Cell 135, 1130–1142 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhang, Y. & Jasin, M. An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway. Nature Struct. Mol. Biol. 18, 80–84 (2011). Using a chromosome translocation reporter system, this paper showed that the putative exonuclease CtIP has a role in promoting chromosome translocations by an alternative end-joining pathway, potentially by exposing microhomology at breakpoints through end resection.

    Article  CAS  Google Scholar 

  56. Rass, E. et al. Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells. Nature Struct. Mol. Biol. 16, 819–824 (2009).

    Article  CAS  Google Scholar 

  57. Xie, A., Kwok, A. & Scully, R. Role of mammalian Mre11 in classical and alternative nonhomologous end joining. Nature Struct. Mol. Biol. 16, 814–818 (2009).

    Article  CAS  Google Scholar 

  58. Bothmer, A. et al. Mechanism of DNA resection during intrachromosomal recombination and immunoglobulin class switching. J. Exp. Med. 210, 115–123 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Fattah, F. et al. Ku regulates the non-homologous end joining pathway choice of DNA double-strand break repair in human somatic cells. PLoS Genet. 6, e1000855 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Liang, L. et al. Human DNA ligases I and III, but not ligase IV, are required for microhomology-mediated end joining of DNA double-strand breaks. Nucleic Acids Res. 36, 3297–3310 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Simsek, D. et al. DNA ligase III promotes alternative nonhomologous end-joining during chromosomal translocation formation. PLoS Genet. 7, e1002080 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Boboila, C. et al. Robust chromosomal DNA repair via alternative end-joining in the absence of X-ray repair cross-complementing protein 1 (XRCC1). Proc. Natl Acad. Sci. USA 109, 2473–2478 (2012). References 61 and 62 attempt to find the genetic requirements for the A-EJ pathway, which seems to mediate a subset of chromosome rearrangements in cancer cells.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Brunet, E. et al. Chromosomal translocations induced at specified loci in human stem cells. Proc. Natl Acad. Sci. USA 106, 10620–10625 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Robbiani, D. F. et al. AID is required for the chromosomal breaks in c-myc that lead to c-myc/IgH translocations. Cell 135, 1028–1038 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chiang, C. et al. Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration. Nature Genet. 44, 390–397 (2012). Another interesting report using next-generation sequencing that showed that balanced chromosome translocations frequently involve sequence from multiple chromosomes. This finding indicates that a model involving simple joining of double-strand breaks on different chromosomes may not account for the complexity of cancer-associated translocations. This report also showed that a minority of rearrangement breakpoints involved microhomology, suggesting that C-NHEJ may cause most translocations.

    Article  CAS  PubMed  Google Scholar 

  66. Huertas, P. DNA resection in eukaryotes: deciding how to fix the break. Nature Struct. Mol. Biol. 17, 11–16 (2010).

    Article  CAS  Google Scholar 

  67. Symington, L. S. & Gautier, J. Double-strand break end resection and repair pathway choice. Annu. Rev. Genet. 45, 247–271 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Frank-Vaillant, M. & Marcand, S. Transient stability of DNA ends allows nonhomologous end joining to precede homologous recombination. Mol. Cell 10, 1189–1199 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Kim, J. S. et al. Independent and sequential recruitment of NHEJ and HR factors to DNA damage sites in mammalian cells. J. Cell Biol. 170, 341–347 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mao, Z., Bozzella, M., Seluanov, A. & Gorbunova, V. Comparison of nonhomologous end joining and homologous recombination in human cells. DNA Repair (Amst.) 7, 1765–1771 (2008).

    Article  CAS  Google Scholar 

  71. Pierce, A. J., Hu, P., Han, M., Ellis, N. & Jasin, M. Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev. 15, 3237–3242 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Difilippantonio, S. et al. 53BP1 facilitates long-range DNA end-joining during V(D)J recombination. Nature 456, 529–533 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Helmink, B. A. et al. H2AX prevents CtIP-mediated DNA end resection and aberrant repair in G1-phase lymphocytes. Nature 469, 245–249 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Manis, J. P. et al. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nature Immunol. 5, 481–487 (2004).

    Article  CAS  Google Scholar 

  75. Ward, I. M. et al. 53BP1 is required for class switch recombination. J. Cell Biol. 165, 459–464 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bothmer, A. et al. Regulation of DNA end joining, resection, and immunoglobulin class switch recombination by 53BP1. Mol. Cell 42, 319–329 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bouwman, P. et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nature Struct. Mol. Biol. 17, 688–695 (2010).

    Article  CAS  Google Scholar 

  78. Sfeir, A. & de Lange, T. Removal of shelterin reveals the telomere end-protection problem. Science 336, 593–597 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Buonomo, S. B., Wu, Y., Ferguson, D. & de Lange, T. Mammalian Rif1 contributes to replication stress survival and homology-directed repair. J. Cell Biol. 187, 385–398 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chapman, J. R. et al. RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol. Cell 49, 858–871 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Di Virgilio, M. et al. Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science 339, 711–715 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Escribano-Diaz, C. et al. A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol. Cell 49, 872–883 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Zimmermann, M., Lottersberger, F., Buonomo, S. B., Sfeir, A. & de Lange, T. 53BP1 regulates DSB repair using Rif1 to control 5′ end resection. Science 339, 700–704 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Neal, J. A. et al. Inhibition of homologous recombination by DNA-dependent protein kinase requires kinase activity, is titratable, and is modulated by autophosphorylation. Mol. Cell. Biol. 31, 1719–1733 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Shrivastav, M. et al. DNA-PKcs and ATM co-regulate DNA double-strand break repair. DNA Repair (Amst.) 8, 920–929 (2009).

    Article  CAS  Google Scholar 

  86. Zhang, S. et al. Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair. J. Cell Biol. 193, 295–305 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Richardson, C. & Jasin, M. Frequent chromosomal translocations induced by DNA double-strand breaks. Nature 405, 697–700 (2000). This report describes an experimental system in embryonic stem cells for testing factors that contribute to translocations. The authors report that the presence of DNA double-strand breaks on different chromosomes significantly increases the rate of translocation.

    Article  CAS  PubMed  Google Scholar 

  88. Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Ramiro, A. R. et al. AID is required for c-myc/IgH chromosome translocations in vivo. Cell 118, 431–438 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Ramiro, A. R. et al. Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature 440, 105–109 (2006). A landmark paper confirming the dependency of IGH MYC translocation on the ability of AID to make DNA double-strand breaks and demonstrating that mutations that decrease the elimination of DNA double-strand breaks cause an increase in translocation frequency.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Misteli, T. Higher-order genome organization in human disease. Cold Spring Harb. Perspect. Biol. 2, a000794 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Osborne, C. S. et al. Myc dynamically and preferentially relocates to a transcription factory occupied by Igh. PLoS Biol. 5, e192 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Roix, J. J., McQueen, P. G., Munson, P. J., Parada, L. A. & Misteli, T. Spatial proximity of translocation-prone gene loci in human lymphomas. Nature Genet. 34, 287–291 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Rocha, P. P. et al. Close proximity to Igh is a contributing factor to AID-mediated translocations. Mol. Cell 47, 873–885 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhang, Y. et al. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell 148, 908–921 (2012). Combining high-throughput chromosome conformation capture and translocation sequencing, this group directly tested the hypothesis that nuclear architecture is a contributor to translocation frequency. They conclude that the relative proximity of chromosomes in the nucleus can affect the frequency of translocations between those chromosomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Mahowald, G. K. et al. Aberrantly resolved RAG-mediated DNA breaks in Atm-deficient lymphocytes target chromosomal breakpoints in cis. Proc. Natl Acad. Sci. USA 106, 18339–18344 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Jackson, A. L. & Loeb, L. A. The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutat. Res. 477, 7–21 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Arlt, M. F., Durkin, S. G., Ragland, R. L. & Glover, T. W. Common fragile sites as targets for chromosome rearrangements. DNA Repair (Amst.) 5, 1126–1135 (2006).

    Article  CAS  Google Scholar 

  99. Ozeri-Galai, E., Bester, A. C. & Kerem, B. The complex basis underlying common fragile site instability in cancer. Trends Genet. 28, 295–302 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Bester, A. C. et al. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 145, 435–446 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Barlow, J. H. et al. Identification of early replicating fragile sites that contribute to genome instability. Cell 152, 620–632 (2013). This report identifies a new class of genomic sites — ERFSs — that are particularly frequently subject to DNA double-strand breaks following replication stress. Owing to their frequency of undergoing DNA breakage, ERFSs represent potential hotspots for translocation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Helmrich, A., Ballarino, M. & Tora, L. Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol. Cell 44, 966–977 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Cowell, I. G. et al. γH2AX foci form preferentially in euchromatin after ionising-radiation. PLoS ONE 2, e1057 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kim, J. A., Kruhlak, M., Dotiwala, F., Nussenzweig, A. & Haber, J. E. Heterochromatin is refractory to γ-H2AX modification in yeast and mammals. J. Cell Biol. 178, 209–218 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Goodarzi, A. A. et al. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol. Cell 31, 167–177 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Ayoub, N., Jeyasekharan, A. D. & Venkitaraman, A. R. Mobilization and recruitment of HP1: a bimodal response to DNA breakage. Cell Cycle 8, 2945–2950 (2009).

    PubMed  Google Scholar 

  111. Luijsterburg, M. S. et al. Heterochromatin protein 1 is recruited to various types of DNA damage. J. Cell Biol. 185, 577–586 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zarebski, M., Wiernasz, E. & Dobrucki, J. W. Recruitment of heterochromatin protein 1 to DNA repair sites. Cytometry A 75, 619–625 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Baldeyron, C., Soria, G., Roche, D., Cook, A. J. & Almouzni, G. HP1α recruitment to DNA damage by p150CAF-1 promotes homologous recombination repair. J. Cell Biol. 193, 81–95 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sallmyr, A., Tomkinson, A. E. & Rassool, F. V. Up-regulation of WRN and DNA ligase IIIα in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks. Blood 112, 1413–1423 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Edwards, S. L. et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451, 1111–1115 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Sakai, W. et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451, 1116–1120 (2008). References 115 and 116 demonstrated the potentially dangerous effect of end-joining pathways in promoting intrachromosomal rearrangements that allow recovery of BRCA2 function in cancer cells challenged with chemotherapy. An A-EJ pathway is implicated in the development of chemoresistance based on the presence of microhomology at the breakpoints of novel mutations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Chen, X. et al. Rational design of human DNA ligase inhibitors that target cellular DNA replication and repair. Cancer Res. 68, 3169–3177 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Srivastava, M. et al. An inhibitor of nonhomologous end-joining abrogates double-strand break repair and impedes cancer progression. Cell 151, 1474–1487 (2012). Using specific inhibitors of a mammalian DNA ligase enzyme, this paper shows that targeting NHEJ can have anticancer effects in combination therapy. This demonstrates the feasibility of using drugs that manipulate DNA repair pathways to achieve therapeutic goals.

    Article  CAS  PubMed  Google Scholar 

  119. Davidson, D. et al. Irinotecan and DNA-PKcs inhibitors synergize in killing of colon cancer cells. Invest. New Drugs 30, 1248–1256 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. de Lange, T. et al. Structure and variability of human chromosome ends. Mol. Cell. Biol. 10, 518–527 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Hastie, N. D. et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866–868 (1990).

    Article  CAS  PubMed  Google Scholar 

  122. d'Adda di Fagagna, F. et al. Effects of DNA nonhomologous end-joining factors on telomere length and chromosomal stability in mammalian cells. Curr. Biol. 11, 1192–1196 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Artandi, S. E. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Artandi, S. E. & DePinho, R. A. Telomeres and telomerase in cancer. Carcinogenesis 31, 9–18 (2010).

    Article  CAS  PubMed  Google Scholar 

  125. Gisselsson, D. et al. Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc. Natl Acad. Sci. USA 97, 5357–5362 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Celli, G. B. & de Lange, T. DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion. Nature Cell Biol. 7, 712–718 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Celli, G. B., Denchi, E. L. & de Lange, T. Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination. Nature Cell Biol. 8, 885–890 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Smogorzewska, A., Karlseder, J., Holtgreve-Grez, H., Jauch, A. & de Lange, T. DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2. Curr. Biol. 12, 1635–1644 (2002).

    Article  CAS  PubMed  Google Scholar 

  129. Rai, R. et al. The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres. EMBO J. 29, 2598–2610 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Maser, R. S. et al. DNA-dependent protein kinase catalytic subunit is not required for dysfunctional telomere fusion and checkpoint response in the telomerase-deficient mouse. Mol. Cell. Biol. 27, 2253–2265 (2007).

    Article  CAS  PubMed  Google Scholar 

  131. Callen, E. et al. 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell 20 May 2013 (doi:10.1016/j.cell.2013.05.023). This study shows that the different activities of 53BP1 in modulating double-strand break resection and promoting NHEJ are dependent on RIF1 and PTIP, which bind separate ATM-dependent phosphorylation sites on 53BP1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

S.F.B. is a recipient of NCI R00 award RCA160574A. A.N. was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the Center for Cancer Research, and by a Department of Defense grant (BC102335).

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Correspondence to Samuel F. Bunting or Andre Nussenzweig.

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Glossary

Non-homologous end-joining

(NHEJ). Joining of DNA double-strand breaks without extensive sequence homology by ligation of DNA ends.

Chromothrypsis

A highly complex chromosome rearrangement event characterized by extensive re-assortment of genetic fragments from one or more chromosomes.

Break-induced replication

(BIR). A modified homology-based repair pathway in which a broken DNA end is repaired by copying a large amount of sequence from an undamaged homologous partner, potentially leading to copying of the entire homologous sequence from the site of damage to the end of the chromosome.

Non-allelic homologous recombination

(NAHR). Recombination between repetitive regions at different genomic sites that leads to chromosome rearrangements, as seen in genetic diseases such as Charcot–Marie–Tooth syndrome.

Class switch recombination

(CSR). A region-specific deletional recombination reaction that replaces one switch region with another. This allows the production of different immunoglobulin isotypes.

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Bunting, S., Nussenzweig, A. End-joining, translocations and cancer. Nat Rev Cancer 13, 443–454 (2013). https://doi.org/10.1038/nrc3537

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