End-joining, translocations and cancer (original) (raw)

• Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
  Article CAS PubMed Google Scholar
• 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
• Giardino, D. et al. De novo balanced chromosome rearrangements in prenatal diagnosis. Prenat Diagn. 29, 257–265 (2009).
  Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• Rabbitts, T. H. Commonality but diversity in cancer gene fusions. Cell 137, 391–395 (2009).
  Article CAS PubMed Google Scholar
• 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
• 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.
• 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
• 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
• 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
• Cancer Genome Atlas Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012).
• 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
• Krzywinski, M. et al. Circos: an information aesthetic for comparative genomics. Genome Res. 19, 1639–1645 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• 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
• 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
• Berger, M. F. et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature 485, 502–506 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• 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
• 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
• 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
• Smith, C. E., Llorente, B. & Symington, L. S. Template switching during break-induced replication. Nature 447, 102–105 (2007).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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.
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Huertas, P. DNA resection in eukaryotes: deciding how to fix the break. Nature Struct. Mol. Biol. 17, 11–16 (2010).
  Article CAS Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Misteli, T. Higher-order genome organization in human disease. Cold Spring Harb. Perspect. Biol. 2, a000794 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Edwards, S. L. et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451, 1111–1115 (2008).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• Hastie, N. D. et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866–868 (1990).
  Article CAS PubMed Google Scholar
• 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
• 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
• Artandi, S. E. & DePinho, R. A. Telomeres and telomerase in cancer. Carcinogenesis 31, 9–18 (2010).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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