Antigen receptor diversification and chromosome translocations (original) (raw)

• Meffre, E., Casellas, R. & Nussenzweig, M.C. Antibody regulation of B cell development. Nat. Immunol. 1, 379–385 (2000).
  CAS PubMed Google Scholar
• Fugmann, S.D., Lee, A.I., Shockett, P.E., Villey, I.J. & Schatz, D.G. The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu. Rev. Immunol. 18, 495–527 (2000).
  CAS PubMed Google Scholar
• Brandt, V.L. & Roth, D.B.V. (D)J recombination: how to tame a transposase. Immunol. Rev. 200, 249–260 (2004).
  CAS PubMed Google Scholar
• Alt, F.W. et al. Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J. 3, 1209–1219 (1984).
  CAS PubMed PubMed Central Google Scholar
• Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).
  CAS PubMed Google Scholar
• Gay, D., Saunders, T., Camper, S. & Weigert, M. Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177, 999–1008 (1993).
  CAS PubMed Google Scholar
• Tiegs, S.L., Russell, D.M. & Nemazee, D. Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177, 1009–1020 (1993).
  CAS PubMed Google Scholar
• Casellas, R. et al. Contribution of receptor editing to the antibody repertoire. Science 291, 1541–1544 (2001).
  CAS PubMed Google Scholar
• Schwickert, T.A. et al. In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446, 83–87 (2007).
  CAS PubMed Google Scholar
• Stavnezer, J. Antibody class switching. Adv. Immunol. 61, 79–146 (1996).
  CAS PubMed Google Scholar
• Kinoshita, K., Harigai, M., Fagarasan, S., Muramatsu, M. & Honjo, T. A hallmark of active class switch recombination: transcripts directed by I promoters on looped-out circular DNAs. Proc. Natl. Acad. Sci. USA 98, 12620–12623 (2001).
  CAS PubMed PubMed Central Google Scholar
• Zarrin, A.A. et al. Antibody class switching mediated by yeast endonuclease-generated DNA breaks. Science 315, 377–381 (2007).
  CAS PubMed Google Scholar
• Muramatsu, M. et al. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J. Biol. Chem. 274, 18470–18476 (1999).
  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).
  CAS PubMed Google Scholar
• Revy, P. et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102, 565–575 (2000).
  CAS PubMed Google Scholar
• Petersen-Mahrt, S.K., Harris, R.S. & Neuberger, M.S. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418, 99–103 (2002).
  CAS PubMed Google Scholar
• Di Noia, J. & Neuberger, M.S. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 419, 43–48 (2002).
  CAS PubMed Google Scholar
• Rada, C., Di Noia, J.M. & Neuberger, M.S. Mismatch recognition and uracil excision provide complementary paths to both Ig switching and the A/T-focused phase of somatic mutation. Mol. Cell 16, 163–171 (2004).
  CAS PubMed Google Scholar
• Ramiro, A.R., Stavropoulos, P., Jankovic, M. & Nussenzweig, M.C. Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand. Nat. Immunol. 4, 452–456 (2003).
  CAS PubMed Google Scholar
• Dickerson, S.K., Market, E., Besmer, E. & Papavasiliou, F.N. AID mediates hypermutation by deaminating single stranded DNA. J. Exp. Med. 197, 1291–1296 (2003).
  CAS PubMed PubMed Central Google Scholar
• Chaudhuri, J. et al. Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature 422, 726–730 (2003).
  CAS PubMed Google Scholar
• Bransteitter, R., Pham, P., Scharff, M.D. & Goodman, M.F. Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proc. Natl. Acad. Sci. USA 100, 4102–4107 (2003).
  CAS PubMed PubMed Central Google Scholar
• Barreto, V.M. et al. AID from bony fish catalyzes class switch recombination. J. Exp. Med. 202, 733–738 (2005).
  CAS PubMed PubMed Central Google Scholar
• Ichikawa, H.T. et al. Structural phylogenetic analysis of activation-induced deaminase function. J. Immunol. 177, 355–361 (2006).
  CAS PubMed Google Scholar
• Wakae, K. et al. Evolution of class switch recombination function in fish activation-induced cytidine deaminase, AID. Int. Immunol. 18, 41–47 (2006).
  CAS PubMed Google Scholar
• Petersen, S. et al. AID is required to initiate Nbs1/γ-H2AX focus formation and mutations at sites of class switching. Nature 414, 660–665 (2001).
  CAS PubMed PubMed Central Google Scholar
• Honjo, T., Nagaoka, H., Shinkura, R. & Muramatsu, M. AID to overcome the limitations of genomic information. Nat. Immunol. 6, 655–661 (2005).
  CAS PubMed Google Scholar
• Schrader, C.E., Linehan, E.K., Mochegova, S.N., Woodland, R.T. & Stavnezer, J. Inducible DNA breaks in Ig S regions are dependent on AID and UNG. J. Exp. Med. 202, 561–568 (2005).
  CAS PubMed PubMed Central Google Scholar
• Larson, E.D., Cummings, W.J., Bednarski, D.W. & Maizels, N. MRE11/RAD50 cleaves DNA in the AID/UNG-dependent pathway of immunoglobulin gene diversification. Mol. Cell 20, 367–375 (2005).
  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).
  CAS Google Scholar
• Adams, J.M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985).
  CAS PubMed Google Scholar
• Strasser, A. et al. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc. Natl. Acad. Sci. USA 88, 8661–8665 (1991).
  CAS PubMed PubMed Central Google Scholar
• Madisen, L. & Groudine, M. Identification of a locus control region in the immunoglobulin heavy-chain locus that deregulates c-myc expression in plasmacytoma and Burkitt's lymphoma cells. Genes Dev. 8, 2212–2226 (1994).
  CAS PubMed Google Scholar
• Kuppers, R. & Dalla-Favera, R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580–5594 (2001).
  CAS PubMed Google Scholar
• Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nat. Rev. Cancer 3, 155–168 (2003).
  CAS PubMed Google Scholar
• Borghesani, P.R. et al. Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc. Natl. Acad. Sci. USA 97, 3336–3341 (2000).
  CAS PubMed PubMed Central Google Scholar
• Elson, A. et al. Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc. Natl. Acad. Sci. USA 93, 13084–13089 (1996).
  CAS PubMed PubMed Central Google Scholar
• Xu, Y. et al. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10, 2411–2422 (1996).
  CAS PubMed Google Scholar
• Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159–171 (1996).
  CAS PubMed Google Scholar
• Liyanage, M. et al. Abnormal rearrangement within the α/δ T-cell receptor locus in lymphomas from Atm-deficient mice. Blood 96, 1940–1946 (2000).
  CAS PubMed Google Scholar
• Callén, E. et al. ATM prevents persistence and propagation of chromosome breaks in lymphocytes. Cell advance online publication, 28 June 2007 (doi:10.1016/j.cell.2007.06.016).
  Google Scholar
• Liao, M.J. & Van Dyke, T. Critical role for Atm in suppressing V(D)J recombination-driven thymic lymphoma. Genes Dev. 13, 1246–1250 (1999).
  CAS PubMed PubMed Central Google Scholar
• Petiniot, L.K. et al. RAG-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice. Mol. Cell. Biol. 22, 3174–3177 (2002).
  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).
  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).
  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).
  CAS PubMed 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).
  CAS PubMed Google Scholar
• Gladdy, R.A. et al. The RAG-1/2 endonuclease causes genomic instability and controls CNS complications of lymphoblastic leukemia in p53/Prkdc-deficient mice. Cancer Cell 3, 37–50 (2003).
  CAS PubMed Google Scholar
• Raghavan, S.C., Kirsch, I.R. & Lieber, M.R. Analysis of the V(D)J recombination efficiency at lymphoid chromosomal translocation breakpoints. J. Biol. Chem. 276, 29126–29133 (2001).
  CAS PubMed Google Scholar
• Marculescu, R., Le, T., Simon, P., Jaeger, U. & Nadel, B.V. (D)J-mediated translocations in lymphoid neoplasms: a functional assessment of genomic instability by cryptic sites. J. Exp. Med. 195, 85–98 (2002).
  CAS PubMed PubMed Central Google Scholar
• Raghavan, S.C., Swanson, P.C., Wu, X., Hsieh, C.L. & Lieber, M.R. A non-B-DNA structure at the Bcl-2 major breakpoint region is cleaved by the RAG complex. Nature 428, 88–93 (2004).
  CAS PubMed Google Scholar
• Lee, G.S., Neiditch, M.B., Salus, S.S. & Roth, D.B. RAG proteins shepherd double-strand breaks to a specific pathway, suppressing error-prone repair, but RAG nicking initiates homologous recombination. Cell 117, 171–184 (2004).
  CAS PubMed Google Scholar
• Dorsett, Y. et al. A role for AID in chromosome translocations between c-myc and the IgH variable region. J. Exp. Med. (in the press).
• Jankovic, M., Casellas, R., Yannoutsos, N., Wardemann, H. & Nussenzweig, M.C. RAGs and regulation of autoantibodies. Annu. Rev. Immunol. 22, 485–501 (2004).
  CAS PubMed Google Scholar
• Potter, M. Neoplastic development in plasma cells. Immunol. Rev. 194, 177–195 (2003).
  CAS PubMed Google Scholar
• Suematsu, S. et al. Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice. Proc. Natl. Acad. Sci. USA 89, 232–235 (1992).
  CAS PubMed PubMed Central Google Scholar
• Potter, M. & Wiener, F. Plasmacytomagenesis in mice: model of neoplastic development dependent upon chromosomal translocations. Carcinogenesis 13, 1681–1697 (1992).
  CAS PubMed Google Scholar
• Unniraman, S., Zhou, S. & Schatz, D.G. Identification of an AID-independent pathway for chromosomal translocations between the Igh switch region and Myc. Nat. Immunol. 5, 1117–1123 (2004).
  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).
  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).
  CAS PubMed PubMed Central Google Scholar
• Gordon, M.S., Kanegai, C.M., Doerr, J.R. & Wall, R. Somatic hypermutation of the B cell receptor genes B29 (Igβ, CD79b) and mb1 (Igα, CD79a). Proc. Natl. Acad. Sci. USA 100, 4126–4131 (2003).
  CAS PubMed PubMed Central Google Scholar
• Shen, H.M., Peters, A., Baron, B., Zhu, X. & Storb, U. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 280, 1750–1752 (1998).
  CAS PubMed Google Scholar
• Wyman, C. & Kanaar, R. DNA double-strand break repair: all's well that ends well. Annu. Rev. Genet. 40, 363–383 (2006).
  CAS PubMed Google Scholar
• Goossens, T., Klein, U. & Kuppers, R. Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease. Proc. Natl. Acad. Sci. USA 95, 2463–2468 (1998).
  CAS PubMed PubMed Central Google Scholar
• Wilson, P.C. et al. Somatic hypermutation introduces insertions and deletions into immunoglobulin V genes. J. Exp. Med. 187, 59–70 (1998).
  CAS PubMed PubMed Central Google Scholar
• Sale, J.E. & Neuberger, M.S. TdT-accessible breaks are scattered over the immunoglobulin V domain in a constitutively hypermutating B cell line. Immunity 9, 859–869 (1998).
  CAS PubMed Google Scholar
• Papavasiliou, F.N. & Schatz, D.G. Cell-cycle-regulated DNA double-stranded breaks in somatic hypermutation of immunoglobulin genes. Nature 408, 216–221 (2000).
  CAS PubMed Google Scholar
• Kong, Q. & Maizels, N. DNA breaks in hypermutating immunoglobulin genes: evidence for a break-and-repair pathway of somatic hypermutation. Genetics 158, 369–378 (2001).
  CAS PubMed PubMed Central Google Scholar
• Bross, L., Muramatsu, M., Kinoshita, K., Honjo, T. & Jacobs, H. DNA double-strand breaks: prior to but not sufficient in targeting hypermutation. J. Exp. Med. 195, 1187–1192 (2002).
  CAS PubMed PubMed Central Google Scholar
• Ronai, D. et al. Detection of chromatin-associated single-stranded DNA in regions targeted for somatic hypermutation. J. Exp. Med. 204, 181–190 (2007).
  CAS PubMed PubMed Central Google Scholar
• Kotani, A. et al. A target selection of somatic hypermutations is regulated similarly between T and B cells upon activation-induced cytidine deaminase expression. Proc. Natl. Acad. Sci. USA 102, 4506–4511 (2005).
  CAS PubMed PubMed Central Google Scholar
• Okazaki, I.M. et al. Constitutive expression of AID leads to tumorigenesis. J. Exp. Med. 197, 1173–1181 (2003).
  CAS PubMed PubMed Central Google Scholar
• Kotani, A. et al. Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice. Proc. Natl. Acad. Sci. USA 104, 1616–1620 (2007).
  PubMed PubMed Central Google Scholar
• Endo, Y. et al. Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling. Oncogene advance online publication; 2 April 2007 (doi:10.1038/sj.onc.1210344). (2007).
  Google Scholar
• Matsumoto, Y. et al. Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat. Med. 13, 470–476 (2007).
  CAS PubMed Google Scholar
• Abraham, R.T. PI 3-kinase related kinases: 'big' players in stress-induced signaling pathways. DNA Repair (Amst.) 3, 883–887 (2004).
  CAS Google Scholar
• Sancar, A., Lindsey-Boltz, L.A., Unsal-Kacmaz, K. & Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73, 39–85 (2004).
  CAS PubMed Google Scholar
• Falck, J., Coates, J. & Jackson, S.P. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434, 605–611 (2005).
  CAS PubMed Google Scholar
• Zhou, J., Lim, C.U., Li, J.J., Cai, L. & Zhang, Y. The role of NBS1 in the modulation of PIKK family proteins ATM and ATR in the cellular response to DNA damage. Cancer Lett. 243, 9–15 (2006).
  CAS PubMed PubMed Central Google Scholar
• Pan-Hammarstrom, Q. et al. Disparate roles of ATR and ATM in immunoglobulin class switch recombination and somatic hypermutation. J. Exp. Med. 203, 99–110 (2006).
  PubMed PubMed Central Google Scholar
• Stracker, T.H., Theunissen, J.W., Morales, M. & Petrini, J.H. The Mre11 complex and the metabolism of chromosome breaks: the importance of communicating and holding things together. DNA Repair (Amst.) 3, 845–854 (2004).
  CAS Google Scholar
• Fernandez-Capetillo, O., Lee, A., Nussenzweig, M. & Nussenzweig, A. H2AX: the histone guardian of the genome. DNA Repair (Amst.) 3, 959–967 (2004).
  CAS Google Scholar
• Chen, H.T. et al. Response to RAG-mediated VDJ cleavage by NBS1 and γ-H2AX. Science 290, 1962–1965 (2000).
  CAS PubMed PubMed Central Google Scholar
• Celeste, A. et al. Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat. Cell Biol. 5, 675–679 (2003).
  CAS PubMed Google Scholar
• Difilippantonio, S. et al. Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models. Nat. Cell Biol. 7, 675–685 (2005).
  CAS PubMed Google Scholar
• Hsieh, C.L., Arlett, C.F. & Lieber, M.R.V. (D)J recombination in ataxia telangiectasia, Bloom's syndrome, and a DNA ligase I-associated immunodeficiency disorder. J. Biol. Chem. 268, 20105–20109 (1993).
  CAS PubMed Google Scholar
• Perkins, E.J. et al. Sensing of intermediates in V(D)J recombination by ATM. Genes Dev. 16, 159–164 (2002).
  CAS PubMed PubMed Central Google Scholar
• Bredemeyer, A.L. et al. ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature 442, 466–470 (2006).
  CAS PubMed Google Scholar
• McKinnon, P.J. ATM and ataxia telangiectasia. EMBO Rep. 5, 772–776 (2004).
  CAS PubMed PubMed Central Google Scholar
• Lumsden, J.M. et al. Immunoglobulin class switch recombination is impaired in Atm-deficient mice. J. Exp. Med. 200, 1111–1121 (2004).
  CAS PubMed PubMed Central Google Scholar
• Reina-San-Martin, B., Chen, H.T., Nussenzweig, A. & Nussenzweig, M.C. ATM is required for efficient recombination between immunoglobulin switch regions. J. Exp. Med. 200, 1103–1110 (2004).
  CAS PubMed PubMed Central Google Scholar
• Franco, S. et al. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol. Cell 21, 201–214 (2006).
  CAS PubMed Google Scholar
• Lee, J.H. & Paull, T.T. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308, 551–554 (2005).
  CAS PubMed Google Scholar
• Difilippantonio, M. J. et al. Distinct domains in Nbs1 regulate irradiation-induced checkpoints and apoptosis. J. Exp. Med. 204, 1003–1011 (2007).
  CAS PubMed PubMed Central Google Scholar
• Varon, R. et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93, 467–476 (1998).
  CAS PubMed Google Scholar
• Carney, J.P. et al. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93, 477–486 (1998).
  CAS PubMed Google Scholar
• Zhu, J., Petersen, S., Tessarollo, L. & Nussenzweig, A. Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. Curr. Biol. 11, 105–109 (2001).
  CAS PubMed Google Scholar
• Kang, J., Bronson, R.T. & Xu, Y. Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair. EMBO J. 21, 1447–1455 (2002).
  CAS PubMed PubMed Central Google Scholar
• Williams, B.R. et al. A murine model of Nijmegen breakage syndrome. Curr. Biol. 12, 648–653 (2002).
  CAS PubMed Google Scholar
• Yeo, T.C. et al. V(D)J rearrangement in Nijmegen breakage syndrome. Mol. Immunol. 37, 1131–1139 (2000).
  CAS PubMed Google Scholar
• Harfst, E. et al. Normal V(D)J recombination in cells from patients with Nijmegen breakage syndrome. Mol. Immunol. 37, 915–929 (2000).
  CAS PubMed Google Scholar
• Gregorek, H., Chrzanowska, K.H., Michalkiewicz, J., Syczewska, M. & Madalinski, K. Heterogeneity of humoral immune abnormalities in children with Nijmegen breakage syndrome: an 8-year follow-up study in a single centre. Clin. Exp. Immunol. 130, 319–324 (2002).
  CAS PubMed PubMed Central Google Scholar
• Reina-San-Martin, B., Nussenzweig, M.C., Nussenzweig, A. & Difilippantonio, S. Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1. Proc. Natl. Acad. Sci. USA 102, 1590–1595 (2005).
  CAS PubMed PubMed Central Google Scholar
• Kracker, S. et al. Nibrin functions in Ig class-switch recombination. Proc. Natl. Acad. Sci. USA 102, 1584–1589 (2005).
  CAS PubMed PubMed Central Google Scholar
• Celeste, A. et al. Genomic instability in mice lacking histone H2AX. Science 296, 922–927 (2002).
  CAS PubMed PubMed Central Google Scholar
• Bassing, C.H. et al. Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX. Proc. Natl. Acad. Sci. USA 99, 8173–8178 (2002).
  CAS PubMed PubMed Central Google Scholar
• Celeste, A. et al. H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114, 371–383 (2003).
  CAS PubMed PubMed Central Google Scholar
• Bassing, C.H. et al. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114, 359–370 (2003).
  CAS PubMed Google Scholar
• Reina-San-Martin, B. et al. H2AX is required for recombination between immunoglobulin switch regions but not for intra-switch region recombination or somatic hypermutation. J. Exp. Med. 197, 1767–1778 (2003).
  CAS PubMed PubMed Central Google Scholar
• Ramiro, A.R., Nussenzweig, M.C. & Nussenzweig, A. Switching on chromosomal translocations. Cancer Res. 66, 7837–7839 (2006).
  CAS PubMed Google Scholar
• Mochan, T.A., Venere, M., DiTullio, R.A., Jr & Halazonetis, T.D. 53BP1, an activator of ATM in response to DNA damage. DNA Repair (Amst.) 3, 945–952 (2004).
  CAS Google Scholar
• Huyen, Y. et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432, 406–411 (2004).
  CAS PubMed Google Scholar
• Botuyan, M.V. et al. Structural basis for the methylation state-specific recognition of histone H4–K20 by 53BP1 and Crb2 in DNA repair. Cell 127, 1361–1373 (2006).
  CAS PubMed PubMed Central Google Scholar
• Ward, I.M., Minn, K., Jorda, K.G. & Chen, J. Accumulation of checkpoint protein 53BP1 at DNA breaks involves its binding to phosphorylated histone H2AX. J. Biol. Chem. 278, 19579–19582 (2003).
  CAS PubMed Google Scholar
• Fernandez-Capetillo, O. et al. DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nat. Cell Biol. 4, 993–997 (2002).
  CAS PubMed Google Scholar
• Bekker-Jensen, S., Lukas, C., Melander, F., Bartek, J. & Lukas, J. Dynamic assembly and sustained retention of 53BP1 at the sites of DNA damage are controlled by Mdc1/NFBD1. J. Cell Biol. 170, 201–211 (2005).
  CAS PubMed PubMed Central Google Scholar
• Ward, I.M., Minn, K., van Deursen, J. & Chen, J. p53 Binding protein 53BP1 is required for DNA damage responses and tumor suppression in mice. Mol. Cell. Biol. 23, 2556–2563 (2003).
  CAS PubMed PubMed Central Google Scholar
• Ward, I.M. et al. 53BP1 is required for class switch recombination. J. Cell Biol. 165, 459–464 (2004).
  CAS PubMed PubMed Central Google Scholar
• Manis, J.P. et al. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat. Immunol. 5, 481–487 (2004).
  CAS PubMed Google Scholar
• Morales, J.C. et al. Role for the BRCA1 C-terminal repeats (BRCT) protein 53BP1 in maintaining genomic stability. J. Biol. Chem. 278, 14971–14977 (2003).
  CAS PubMed Google Scholar
• Reina-San-Martin, B., Chen, J., Nussenzweig, A. & Nussenzweig, M.C. Enhanced intra-switch region recombination during immunoglobulin class switch recombination in 53BP1 −/− B cells. Eur. J. Immunol. 37, 235–239 (2007).
  CAS PubMed Google Scholar
• Bassing, C.H. & Alt, F.W. The cellular response to general and programmed DNA double strand breaks. DNA Repair (Amst.) 3, 781–796 (2004).
  CAS Google Scholar
• Lieber, M.R., Ma, Y., Pannicke, U. & Schwarz, K. The mechanism of vertebrate nonhomologous DNA end joining and its role in V(D)J recombination. DNA Repair (Amst.) 3, 817–826 (2004).
  CAS Google Scholar
• Taccioli, G.E. et al. Impairment of V(D)J recombination in double-strand break repair mutants. Science 260, 207–210 (1993).
  CAS PubMed Google Scholar
• Carroll, A.M. & Bosma, M.J. T-lymphocyte development in scid mice is arrested shortly after the initiation of T-cell receptor δ gene recombination. Genes Dev. 5, 1357–1366 (1991).
  CAS PubMed Google Scholar
• Casellas, R. et al. Ku80 is required for immunoglobulin isotype switching. EMBO J. 17, 2404–2411 (1998).
  CAS PubMed PubMed Central Google Scholar
• Manis, J.P. et al. Ku70 is required for late B cell development and immunoglobulin heavy chain class switching. J. Exp. Med. 187, 2081–2089 (1998).
  CAS PubMed PubMed Central Google Scholar
• Burma, S., Chen, B.P. & Chen, D.J. Role of non-homologous end joining (NHEJ) in maintaining genomic integrity. DNA Repair (Amst.) 5, 1042–1048 (2006).
  CAS Google Scholar
• Mills, K.D., Ferguson, D.O. & Alt, F.W. The role of DNA breaks in genomic instability and tumorigenesis. Immunol. Rev. 194, 77–95 (2003).
  CAS PubMed Google Scholar
• Walker, J.R., Corpina, R.A. & Goldberg, J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412, 607–614 (2001).
  CAS PubMed Google Scholar
• Burma, S. & Chen, D.J. Role of DNA-PK in the cellular response to DNA double-strand breaks. DNA Repair (Amst.) 3, 909–918 (2004).
  CAS Google Scholar
• Chen, B.P. et al. Ataxia telangiectasia mutated (ATM) is essential for DNA-PKcs phosphorylations at the Thr-2609 cluster upon DNA double strand break. J. Biol. Chem. 282, 6582–6587 (2007).
  CAS PubMed Google Scholar
• Gladdy, R.A., Nutter, L.M., Kunath, T., Danska, J.S. & Guidos, C.J. p53-Independent apoptosis disrupts early organogenesis in embryos lacking both ataxia-telangiectasia mutated and Prkdc. Mol. Cancer Res. 4, 311–318 (2006).
  CAS PubMed Google Scholar
• Sekiguchi, J. et al. Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development. Proc. Natl. Acad. Sci. USA 98, 3243–3248 (2001).
  CAS PubMed PubMed Central Google Scholar
• Vogel, H., Lim, D.S., Karsenty, G., Finegold, M. & Hasty, P. Deletion of Ku86 causes early onset of senescence in mice. Proc. Natl. Acad. Sci. USA 96, 10770–10775 (1999).
  CAS PubMed PubMed Central Google Scholar
• Nussenzweig, A. et al. Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature 382, 551–555 (1996).
  CAS PubMed Google Scholar
• Gu, Y. et al. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 7, 653–665 (1997).
  CAS PubMed Google Scholar
• Taccioli, G.E. et al. Targeted disruption of the catalytic subunit of the DNA-PK gene in mice confers severe combined immunodeficiency and radiosensitivity. Immunity 9, 355–366 (1998).
  CAS PubMed Google Scholar
• Gao, Y. et al. A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination. Immunity 9, 367–376 (1998).
  CAS PubMed Google Scholar
• Ouyang, H. et al. Ku70 is required for DNA repair but not for T cell antigen receptor gene recombination in vivo. J. Exp. Med. 186, 921–929 (1997).
  CAS PubMed PubMed Central Google Scholar
• Bassing, C.H., Swat, W. & Alt, F.W. The mechanism and regulation of chromosomal V(D)J recombination. Cell 109 Suppl, S45–S55 (2002).
  CAS PubMed Google Scholar
• Grawunder, U. & Harfst, E. How to make ends meet in V(D)J recombination. Curr. Opin. Immunol. 13, 186–194 (2001).
  CAS PubMed Google Scholar
• Bosma, G.C. et al. DNA-dependent protein kinase activity is not required for immunoglobulin class switching. J. Exp. Med. 196, 1483–1495 (2002).
  CAS PubMed PubMed Central Google Scholar
• Cook, A.J. et al. Reduced switching in SCID B cells is associated with altered somatic mutation of recombined S regions. J. Immunol. 171, 6556–6564 (2003).
  CAS PubMed Google Scholar
• Manis, J.P., Dudley, D., Kaylor, L. & Alt, F.W. IgH class switch recombination to IgG1 in DNA-PKcs-deficient B cells. Immunity 16, 607–617 (2002).
  CAS PubMed Google Scholar
• Moshous, D. et al. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105, 177–186 (2001).
  CAS PubMed Google Scholar
• Rooney, S. et al. Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. Mol. Cell 10, 1379–1390 (2002).
  CAS PubMed Google Scholar
• Ma, Y., Pannicke, U., Schwarz, K. & Lieber, M.R. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell 108, 781–794 (2002).
  CAS PubMed Google Scholar
• Lobrich, M. & Jeggo, P.A. Harmonising the response to DSBs: a new string in the ATM bow. DNA Repair (Amst.) 4, 749–759 (2005).
  Google Scholar
• Ma, Y., Schwarz, K. & Lieber, M.R. The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps. DNA Repair (Amst.) 4, 845–851 (2005).
  CAS Google Scholar
• Goodarzi, A.A. et al. DNA-PK autophosphorylation facilitates Artemis endonuclease activity. EMBO J. 25, 3880–3889 (2006).
  CAS PubMed PubMed Central Google Scholar
• Moshous, D. et al. Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J. Clin. Invest. 111, 381–387 (2003).
  CAS PubMed PubMed Central Google Scholar
• Rooney, S. et al. Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells. Proc. Natl. Acad. Sci. USA 101, 2410–2415 (2004).
  CAS PubMed PubMed Central Google Scholar
• Rooney, S., Alt, F.W., Sekiguchi, J. & Manis, J.P. Artemis-independent functions of DNA-dependent protein kinase in Ig heavy chain class switch recombination and development. Proc. Natl. Acad. Sci. USA 102, 2471–2475 (2005).
  CAS PubMed PubMed Central Google Scholar
• Costantini, S., Woodbine, L., Andreoli, L., Jeggo, P.A. & Vindigni, A. Interaction of the Ku heterodimer with the DNA ligase IV/Xrcc4 complex and its regulation by DNA-PK. DNA Repair (Amst) 6, 712–722 (2007).
  CAS Google Scholar
• Mari, P.O. et al. Dynamic assembly of end-joining complexes requires interaction between Ku70/80 and XRCC4. Proc. Natl. Acad. Sci. USA 103, 18597–18602 (2006).
  CAS PubMed PubMed Central Google Scholar
• Gao, Y. et al. A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95, 891–902 (1998).
  CAS PubMed Google Scholar
• Frank, K.M. et al. Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 396, 173–177 (1998).
  CAS PubMed Google Scholar
• Barnes, D.E., Stamp, G., Rosewell, I., Denzel, A. & Lindahl, T. Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice. Curr. Biol. 8, 1395–1398 (1998).
  CAS PubMed Google Scholar
• Lee, Y., Barnes, D.E., Lindahl, T. & McKinnon, P.J. Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm. Genes Dev. 14, 2576–2580 (2000).
  CAS PubMed PubMed Central Google Scholar
• Karanjawala, Z.E. et al. The embryonic lethality in DNA ligase IV-deficient mice is rescued by deletion of Ku: implications for unifying the heterogeneous phenotypes of NHEJ mutants. DNA Repair (Amst.) 1, 1017–1026 (2002).
  CAS Google Scholar
• Ahnesorg, P., Smith, P. & Jackson, S.P. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124, 301–313 (2006).
  CAS PubMed Google Scholar
• Buck, D. et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124, 287–299 (2006).
  CAS PubMed Google Scholar
• Zha, S., Alt, F.W., Cheng, H.L., Brush, J.W. & Li, G. Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficient murine ES cells. Proc. Natl. Acad. Sci. USA 104, 4518–4523 (2007).
  CAS PubMed PubMed Central Google Scholar
• Pan-Hammarstrom, Q. et al. Impact of DNA ligase IV on nonhomologous end joining pathways during class switch recombination in human cells. J. Exp. Med. 201, 189–194 (2005).
  PubMed PubMed Central Google Scholar