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V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining

Oncogene volume 26, pages 7780–7791 (2007)Cite this article

Abstract

The immune system is the site of intense DNA damage/modification, which occur during the development and maturation of B and T lymphocytes. V(D)J recombination is initiated by the Rag1 and Rag2 proteins and the formation of a DNA double-strand break (DNA dsb). This DNA lesion is repaired through the use of the non-homologous end-joining (NHEJ) pathway, several factors of which have been identified through the survey of immunodeficient conditions in humans and mice. Upon antigenic recognition in secondary lymphoid organs, mature B cells further diversify their repertoire through class switch recombination (CSR). CSR is a region-specific rearrangement process triggered by the activation-induced cytidine deaminase factor and also proceeds through the introduction of DNA dsb. However, unlike V(D)J recombination, CSR does not rely strictly on NHEJ for the repair of the DNA lesion. Instead, CSR, but not V(D)J recombination, requires the major factors of the DNA damage response. V(D)J recombination and CSR thus represent an interesting paradigm to study the regulation among the various DNA repair pathways.

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References

  • Ahnesorg P, Jackson SP . (2007). The non-homologous end-joining protein Nej1p is a target of the DNA damage checkpoint. DNA Repair (Amst) 6: 190–201.

    CAS  Google Scholar 

  • Ahnesorg P, Smith P, Jackson SP . (2006). XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124: 301–313.

    CAS  Google Scholar 

  • Aravind L . (1999). An evolutionary classification of the metallo-beta-lactamase fold proteins. In Silico Biol 1: 69–91.

    CAS  Google Scholar 

  • Audebert M, Salles B, Calsou P . (2004). Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J Biol Chem 279: 55117–55126.

    CAS  Google Scholar 

  • Bassing CH, Alt FW . (2004). H2AX may function as an anchor to hold broken chromosomal DNA ends in close proximity. Cell Cycle 3: 149–153.

    Article  CAS  Google Scholar 

  • Ben-Omran TI, Cerosaletti K, Concannon P, Weitzman S, Nezarati MM . (2005). A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome. Am J Med Genet A 137: 283–287.

    Google Scholar 

  • Biedermann KA, Sum JR, Giaccia AJ, Tosto LM, Brown JM . (1991). Scid mutation in mice confers hypersensitivity to ionizing radiation and a deficiency in DNA double-strand break repair. Proc Natl Acad Sci USA 88: 1394–1397.

    CAS  Google Scholar 

  • Bosma GC, Custer RP, Bosma MJ . (1983). A severe combined immunodeficiency mutation in the mouse. Nature 301: 527–530.

    CAS  Google Scholar 

  • Bosma GC, Kim J, Urich T, Fath DM, Cotticelli MG, Ruetsch NR et al. (2002). DNA-dependent protein kinase activity is not required for immunoglobulin class switching. J Exp Med 196: 1483–1495.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Buck D, Malivert L, de Chasseval R, Barraud A, Fondaneche MC, Sanal O et al. (2006a). Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124: 287–299.

    CAS  Google Scholar 

  • Buck D, Moshous D, de Chasseval R, Ma Y, le Deist F, Cavazzana-Calvo M et al. (2006b). Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV. Eur J Immunol 36: 224–235.

    CAS  Google Scholar 

  • Callebaut I, Malivert L, Fischer A, Mornon JP, Revy P, de Villartay JP . (2006). Cernunnos interacts with the XRCC4 × DNA-ligase IV complex and is homologous to the yeast nonhomologous end-joining factor Nej1. J Biol Chem 281: 13857–13860.

    CAS  Google Scholar 

  • Callebaut I, Moshous D, Mornon JP, De Villartay JP . (2002). Metallo-β-lactamase fold within nucleic acids processing enzymes: the β-CASP family. Nucl Acid Res 30: 3592–3601.

    CAS  Google Scholar 

  • Casellas R, Nussenzweig A, Wuerffel R, Pelanda R, Reichlin A, Suh H et al. (1998). Ku80 is required for immunoglobulin isotype switching. EMBO J 17: 2404–2411.

    CAS  Google Scholar 

  • Catalan N, Selz F, Imai K, Revy P, Fischer A, Durandy A . (2003). The block in immunoglobulin class switch recombination caused by activation-induced cytidine deaminase deficiency occurs prior to the generation of DNA double strand breaks in switch mu region. J Immunol 171: 2504–2509.

    CAS  Google Scholar 

  • Cavazzana-Calvo M, Le Deist F, de Saint Basile G, Papadopoulo D, de Villartay JP, Fischer A . (1993). Increased radiosensitivity of granulocyte macrophage colony-forming units and skin fibroblasts in human autosomal recessive severe combined immunodeficiency. J Clin Invest 91: 1214–1218.

    CAS  Google Scholar 

  • Cavero S, Chahwan C, Russell P . (2007). Xlf1 is required for DNA repair by nonhomologous end joining in Schizosaccharomyces pombe. Genetics 175: 963–967.

    CAS  Google Scholar 

  • Chaudhuri J, Alt FW . (2004). Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nat Rev Immunol 4: 541–552.

    CAS  Google Scholar 

  • Chen L, Morio T, Minegishi Y, Nakada S, Nagasawa M, Komatsu K et al. (2005). Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage. Cancer Sci 96: 134–141.

    CAS  Google Scholar 

  • Cook AJ, Oganesian L, Harumal P, Basten A, Brink R, Jolly CJ . (2003). Reduced switching in SCID B cells is associated with altered somatic mutation of recombined S regions. J Immunol 171: 6556–6564.

    CAS  Google Scholar 

  • Corneo B, Wendland RL, Deriano L, Cui X, Klein I, SY W et al. (2007). Rag mutations reveal robust alternative end joining. Nature 449: 483–486.

    CAS  Google Scholar 

  • Dai Y, Kysela B, Hanakahi LA, Manolis K, Riballo E, Stumm M et al. (2003). Nonhomologous end joining and V(D)J recombination require an additional factor. Proc Natl Acad Sci USA 100: 2462–2467.

    CAS  Google Scholar 

  • Darroudi F, Wiegant W, Meijers M, Friedl AA, van der Burg M, Fomina J et al. (2007). Role of Artemis in DSB repair and guarding chromosomal stability following exposure to ionizing radiation at different stages of cell cycle. Mutat Res 615: 111–124.

    CAS  Google Scholar 

  • Deckbar D, Birraux J, Krempler A, Tchouandong L, Beucher A, Walker S et al. (2007). Chromosome breakage after G2 checkpoint release. J Cell Biol 176: 749–755.

    CAS  Google Scholar 

  • Decottignies A . (2007). Microhomology-mediated end joining in fission yeast is repressed by pku70 and relies on genes involved in homologous recombination. Genetics 176: 1403–1415.

    CAS  Google Scholar 

  • Deshpande RA, Wilson TE . (2007). Modes of interaction among yeast Nej1, Lif1 and Dnl4 proteins and comparison to human XLF, XRCC4 and Lig4. DNA Repair 6: 1507–1516.

    CAS  Google Scholar 

  • Drouet J, Frit P, Delteil C, de Villartay JP, Salles B, Calsou P . (2006). Interplay between Ku, Artemis, and the DNA-dependent protein kinase catalytic subunit at DNA ends. J Biol Chem 281: 27784–27793.

    CAS  Google Scholar 

  • Dudley DD, Chaudhuri J, Bassing CH, Alt FW . (2005). Mechanism and control of V(D)J recombination versus class switch recombination: similarities and differences. Adv Immunol 86: 43–112.

    CAS  Google Scholar 

  • Ege M, Ma Y, Manfras B, Kalwak K, Lu H, Lieber MR et al. (2005). Omenn syndrome due to ARTEMIS mutations. Blood 105: 4179–4186.

    CAS  Google Scholar 

  • Enders A, Fisch P, Schwarz K, Duffner U, Pannicke U, Nikolopoulos E et al. (2006). A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. J Immunol 176: 5060–5068.

    CAS  Google Scholar 

  • Evans PM, Woodbine L, Riballo E, Gennery AR, Hubank M, Jeggo PA . (2006). Radiation-induced delayed cell death in a hypomorphic Artemis cell line. Hum Mol Genet 15: 1303–1311.

    CAS  Google Scholar 

  • Fischer A . (2004). Human primary immunodeficiency diseases: a perspective. Nat Immunol 5: 23–30.

    CAS  Google Scholar 

  • Franco S, Alt FW, Manis JP . (2006). Pathways that suppress programmed DNA breaks from progressing to chromosomal breaks and translocations. DNA Repair (Amst) 5: 1030–1041.

    CAS  Google Scholar 

  • Frank KM, Sekiguchi JM, Seidl KJ, Swat W, Rathbun GA, Cheng HL et al. (1998). Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature 396: 173–177.

    CAS  Google Scholar 

  • Frank-Vaillant M, Marcand S . (2001). NHEJ regulation by mating type is exercised through a novel protein, Lif2p, essential to the ligase IV pathway. Genes Dev 15: 3005–3012.

    CAS  Google Scholar 

  • Fulop GM, Phillips RA . (1990). The scid mutation in mice causes a general defect in DNA repair. Nature 347: 479–482.

    CAS  Google Scholar 

  • Gao Y, Sun Y, Frank KM, Dikkes P, Fujiwara Y, Seidl KJ et al. (1998). A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell 95: 891–902.

    CAS  Google Scholar 

  • Geng L, Zhang X, Zheng S, Legerski RJ . (2007). Artemis links ATM to G2/M checkpoint recovery via regulation of Cdk1-cyclin B. Mol Cell Biol 27: 2625–2635.

    CAS  Google Scholar 

  • Gennery AR, Hodges E, Williams AP, Harris S, Villa A, Angus B et al. (2005). Omenn's syndrome occurring in patients without mutations in recombination activating genes. Clin Immunol 116: 246–256.

    CAS  Google Scholar 

  • Goodarzi AA, Yu Y, Riballo E, Douglas P, Walker SA, Ye R et al. (2006). DNA-PK autophosphorylation facilitates Artemis endonuclease activity. EMBO J 25: 3880–3889.

    CAS  Google Scholar 

  • Grawunder U, Wilm M, Wu X, Kulesza P, Wilson TE, Mann M et al. (1997). Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Nature 388: 492–495.

    CAS  Google Scholar 

  • Grawunder U, Zimmer D, Leiber MR . (1998). DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains. Curr Biol 8: 873–876.

    CAS  Google Scholar 

  • Gu J, Lu H, Tsai AG, Schwarz K, Lieber MR . (2007). Single-stranded DNA ligation and XLF-stimulated incompatible DNA end ligation by the XRCC4-DNA ligase IV complex: influence of terminal DNA sequence. Nucleic Acids Res 35: 5755–5762.

    CAS  Google Scholar 

  • Hendrickson EA, Qin XQ, Bump EA, Schatz DG, Oettinger M, Weaver DT . (1991). A link between double-strand break related repair and V(D)J recombination : the scid mutation. Proc Natl Acad Sci USA 88: 4061–4065.

    CAS  Google Scholar 

  • Hentges P, Ahnesorg P, Pitcher RS, Bruce CK, Kysela B, Green AJ et al. (2006). Evolutionary and functional conservation of the DNA non-homologous end-joining protein, XLF/Cernunnos. J Biol Chem 281: 37517–37526.

    CAS  Google Scholar 

  • Imai K, Slupphaug G, Lee WI, Revy P, Nonoyama S, Catalan N et al. (2003). Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol 4: 1023–1028.

    CAS  Google Scholar 

  • Inagaki K, Ma C, Storm TA, Kay MA, Nakai H . (2007). A role of DNA-PKcs and Artemis in opening viral DNA hairpin termini in various tissues in mice. J Virol 81: 11304–11321.

    CAS  Google Scholar 

  • Ishikawa H, Nakagawa N, Kuramitsu S, Masui R . (2006). Crystal structure of TTHA0252 from Thermus thermophilus HB8, a RNA degradation protein of the metallo-beta-lactamase superfamily. J Biochem (Tokyo) 140: 535–542.

    CAS  Google Scholar 

  • Jankovic M, Nussenzweig A, Nussenzweig MC . (2007). Antigen receptor diversification and chromosome translocations. Nat Immunol 8: 801–808.

    CAS  Google Scholar 

  • Junop MS, Modesti M, Guarne A, Ghirlando R, Gellert M, Yang W . (2000). Crystal structure of the Xrcc4 DNA repair protein and implications for end joining. EMBO J 19: 5962–5970.

    CAS  Google Scholar 

  • Kegel A, Sjostrand JO, Astrom SU . (2001). Nej1p, a cell type-specific regulator of nonhomologous end joining in yeast. Curr Biol 11: 1611–1617.

    CAS  Google Scholar 

  • Kiefer K, Oshinsky J, Kim J, Nakajima PB, Bosma GC, Bosma MJ . (2007). The catalytic subunit of DNA-protein kinase (DNA-PKcs) is not required for Ig class-switch recombination. Proc Natl Acad Sci USA 104: 2843–2848.

    CAS  Google Scholar 

  • Kracker S, Bergmann Y, Demuth I, Frappart PO, Hildebrand G, Christine R et al. (2005). Nibrin functions in Ig class-switch recombination. Proc Natl Acad Sci USA 102: 1584–1589.

    CAS  Google Scholar 

  • Krempler A, Deckbar D, Jeggo PA, Lobrich M . (2007). An imperfect G2M checkpoint contributes to chromosome instability following irradiation of S and G2 phase cells. Cell Cycle 6: 1682–1686.

    CAS  Google Scholar 

  • Lee GS, Neiditch MB, Salus SS, Roth DB . (2004). RAG proteins shepherd double-strand breaks to a specific pathway, suppressing error-prone repair, but RAG nicking initiates homologous recombination. Cell 117: 171–184.

    CAS  Google Scholar 

  • Lenain C, Bauwens S, Amiard S, Brunori M, Giraud-Panis MJ, Gilson E . (2006). The Apollo 5′ exonuclease functions together with TRF2 to protect telomeres from DNA repair. Curr Biol 16: 1303–1310.

    CAS  Google Scholar 

  • Li L, Drayna D, Hu D, Hayward A, Gahagan S, Pabst H et al. (1998). The gene for severe combined immunodeficiency disease in Athabascan-speaking native Americans is located on chromosome 10p. Am J Hum Genet 62: 136–144.

    CAS  Google Scholar 

  • Li L, Salido E, Zhou Y, Bhattacharyya S, Yannone SM, Dunn E et al. (2005). Targeted disruption of the Artemis murine counterpart results in SCID and defective V(D)J recombination that is partially corrected with bone marrow transplantation. J Immunol 174: 2420–2428.

    CAS  Google Scholar 

  • Lieber MR, Hesse JE, Lewis S, Bosma GC, Rosenberg N, Mizuuchi K et al. (1988). The defect in murine severe combined immune deficiency: joining of signal sequences but not coding segments in V(D)J recombination. Cell 55: 7–16.

    CAS  Google Scholar 

  • Lu H, Pannicke U, Schwarz K, Lieber MR . (2007). Length-dependent binding of human XLF to DNA and stimulation of XRCC4·DNA ligase IV activity. J Biol Chem 282: 11155–11162.

    CAS  Google Scholar 

  • Lumsden JM, McCarty T, Petiniot LK, Shen R, Barlow C, Wynn TA et al. (2004). Immunoglobulin class switch recombination is impaired in Atm-deficient mice. J Exp Med 200: 1111–1121.

    CAS  Google Scholar 

  • Ma Y, Pannicke U, Lu H, Niewolik D, Schwarz K, Lieber MR . (2005). The DNA-dependent protein kinase catalytic subunit phosphorylation sites in human Artemis. J Biol Chem 280: 33839–33846.

    CAS  Google Scholar 

  • Ma Y, Pannicke U, Schwarz K, Lieber MR . (2002). 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.

    CAS  Google Scholar 

  • Mandel CR, Kaneko S, Zhang H, Gebauer D, Vethantham V, Manley JL et al. (2006). Polyadenylation factor CPSF-73 is the pre-mRNA 3′-end-processing endonuclease. Nature 444: 953–956.

    CAS  Google Scholar 

  • Manis JP, Dudley D, Kaylor L, Alt FW . (2002a). IgH class switch recombination to IgG1 in DNA-PKcs-deficient B cells. Immunity 16: 607–617.

    CAS  Google Scholar 

  • Manis JP, Gu Y, Lansford R, Sonoda E, Ferrini R, Davidson L et al. (1998). Ku70 is required for late B cell development and immunoglobulin heavy chain class switching. J Exp Med 187: 2081–2089.

    CAS  Google Scholar 

  • Manis JP, Morales JC, Xia Z, Kutok JL, Alt FW, Carpenter PB . (2004). 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat Immunol 5: 481–487.

    CAS  Google Scholar 

  • Manis JP, Tian M, Alt FW . (2002b). Mechanism and control of class-switch recombination. Trends Immunol 23: 31–39.

    CAS  Google Scholar 

  • Moshous D, Callebaut I, de Chasseval R, Corneo B, Cavazzana-Calvo M, Le Deist F et al. (2001a). 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.

    CAS  Google Scholar 

  • Moshous D, Callebaut I, de Chasseval R, Corneo B, Cavazzana-Calvo M, Le Deist F et al. (2001b). 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.

    CAS  Google Scholar 

  • Moshous D, Li L, de Chasseval R, Philippe N, Jabado N, Cowan MJ et al. (2000). A new gene involved in DNA double-strand break repair and V(D)J recombination is located on human chromosome 10p. Hum Mol Genet 9: 583–588.

    CAS  Google Scholar 

  • Moshous D, Pannetier C, Chasseval Rd R, Deist Fl F, Cavazzana-Calvo M, Romana S et al. (2003). Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J Clin Invest 111: 381–387.

    CAS  Google Scholar 

  • Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T . (2000). Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102: 553–563.

    CAS  Google Scholar 

  • Nicolas N, Finnie NJ, Cavazzana-Calvo M, Papadopoulo D, Le Deist F, Fischer A et al. (1996). Lack of detectable defect in DNA double-strand break repair and DNA-dependant protein kinase activity in radiosensitive human severe combined immunodeficiency fibroblasts. Eur J Immunol 26: 1118–1122.

    CAS  Google Scholar 

  • Nicolas N, Moshous D, Papadopoulo D, Cavazzana-Calvo M, de Chasseval R, le Deist F et al. (1998). A human SCID condition with increased sensitivity to ionizing radiations and impaired V(D)J rearrangements defines a new DNA recombination/repair deficiency. J Exp Med 188: 627–634.

    CAS  Google Scholar 

  • Niewolik D, Pannicke U, Lu H, Ma Y, Wang LC, Kulesza P et al. (2006). DNA-PKcs dependence of Artemis endonucleolytic activity, differences between hairpins and 5′ or 3′ overhangs. J Biol Chem 281: 33900–33909.

    CAS  Google Scholar 

  • O'Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B et al. (2001). DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell 8: 1175–1185.

    CAS  Google Scholar 

  • Oettinger MA, Schatz DG, Gorka C, Baltimore D . (1990). RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248: 1517–1523.

    CAS  Google Scholar 

  • Ooi SL, Shoemaker DD, Boeke JD . (2001). A DNA microarray-based genetic screen for nonhomologous end-joining mutants in Saccharomyces cerevisiae. Science 294: 2552–2556.

    CAS  Google Scholar 

  • Pan-Hammarstrom Q, Jones AM, Lahdesmaki A, Zhou W, Gatti RA, Hammarstrom L et al. (2005). Impact of DNA ligase IV on nonhomologous end joining pathways during class switch recombination in human cells. J Exp Med 201: 189–194.

    Google Scholar 

  • Pannicke U, Ma Y, Hopfner KP, Niewolik D, Lieber MR, Schwarz K . (2004). Functional and biochemical dissection of the structure-specific nuclease ARTEMIS. EMBO J 23: 1987–1997.

    CAS  Google Scholar 

  • Papavasiliou FN, Schatz DG . (2002). Somatic hypermutation of immunoglobulin genes: merging mechanisms for genetic diversity. Cell 109(Suppl): S35–S44.

    CAS  Google Scholar 

  • Pergola F, Zdzienicka MZ, Lieber MR . (1993). V(D)J recombination in mammalian cell mutants defective in DNA double-strand break repair. Mol Cell Biol 13: 3464–3471.

    CAS  Google Scholar 

  • Peron S, Pan-Hammarstrom Q, Imai K, Du L, Taubenheim N, Sanal O et al. (2007). A primary immunodeficiency characterized by defective immunoglobulin class switch recombination and impaired DNA repair. J Exp Med 204: 1207–1216.

    CAS  Google Scholar 

  • Petersen S, Casellas R, Reina-San-Martin B, Chen HT, Difilippantonio MJ, Wilson PC et al. (2001). AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching. Nature 414: 660–665.

    CAS  Google Scholar 

  • Poinsignon C, de Chasseval R, Soubeyrand S, Moshous D, Fischer A, Hache RJ et al. (2004a). Phosphorylation of Artemis following irradiation-induced DNA damage. Eur J Immunol 34: 3146–3155.

    CAS  Google Scholar 

  • Poinsignon C, Moshous D, Callebaut I, de Chasseval R, Villey I, de Villartay JP . (2004b). The metallo-β-lactamase/β-CASP domain of Artemis constitutes the catalytic core required for V(D)J recombination. J Exp Med 199: 315–321.

    CAS  Google Scholar 

  • Povirk LF, Zhou T, Zhou R, Cowan MJ, Yannone SM . (2007). Processing of 3′-phosphoglycolate-terminated DNA double strand breaks by Artemis nuclease. J Biol Chem 282: 3547–3558.

    CAS  Google Scholar 

  • Rada C, Williams GT, Nilsen H, Barnes DE, Lindahl T, Neuberger MS . (2002). Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr Biol 12: 1748–1755.

    CAS  Google Scholar 

  • Reina-San-Martin B, Chen HT, Nussenzweig A, Nussenzweig MC . (2004). ATM is required for efficient recombination between immunoglobulin switch regions. J Exp Med 200: 1103–1110.

    CAS  Google Scholar 

  • Reina-San-Martin B, Difilippantonio S, Hanitsch L, Masilamani RF, Nussenzweig A, Nussenzweig MC . (2003). 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.

    CAS  Google Scholar 

  • Reina-San-Martin B, Nussenzweig MC, Nussenzweig A, Difilippantonio S . (2005). Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1. Proc Natl Acad Sci USA 102: 1590–1595.

    CAS  Google Scholar 

  • Revy P, Buck D, le Deist F, de Villartay JP . (2005). The repair of DNA damages/modifications during the maturation of the immune system: lessons from human primary immunodeficiency disorders and animal models. Adv Immunol 87: 237–295.

    CAS  Google Scholar 

  • Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O et al. (2000). Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2). Cell 102: 565–575.

    CAS  Google Scholar 

  • Riballo E, Kuhne M, Rief N, Doherty A, Smith GC, Recio MJ et al. (2004). A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Mol Cell 16: 715–724.

    CAS  Google Scholar 

  • Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM . (1998). DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273: 5858–5868.

    CAS  Google Scholar 

  • Rooney S, Alt FW, Sekiguchi J, Manis JP . (2005). 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.

    CAS  Google Scholar 

  • Rooney S, Sekiguchi J, Zhu C, Cheng HL, Manis J, Whitlow S et al. (2002). Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. Mol Cell 10: 1379–1390.

    CAS  Google Scholar 

  • Roth DB . (2003). Restraining the V(D)J recombinase. Nat Rev Immunol 3: 656–666.

    CAS  Google Scholar 

  • Roth DB, Menetski JP, Nakajima PB, Bosma MJ, Gellert M . (1992). V(D)J recombination: broken DNA molecules with covalently sealed (hairpin) coding ends in scid mouse thymocytes. Cell 70: 983–991.

    CAS  Google Scholar 

  • Roth DB, Porter TN, Wilson JH . (1985). Mechanisms of nonhomologous recombination in mammalian cells. Mol Cell Biol 5: 2599–2607.

    CAS  Google Scholar 

  • Rush JS, Fugmann SD, Schatz DG . (2004). Staggered AID-dependent DNA double strand breaks are the predominant DNA lesions targeted to S mu in Ig class switch recombination. Int Immunol 16: 549–557.

    CAS  Google Scholar 

  • Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S . (2004). Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73: 39–85.

    CAS  Google Scholar 

  • Schar P, Herrmann G, Daly G, Lindahl T . (1997). A newly identified DNA ligase of Saccharomyces cerevisiae involved in RAD52-independent repair of DNA double-strand breaks. Genes Dev 11: 1912–1924.

    CAS  Google Scholar 

  • Schatz DG, Oettinger MA, Baltimore D . (1989). The V(D)J recombination activating gene, RAG-1. Cell 59: 1035–1048.

    CAS  Google Scholar 

  • Sibanda BL, Critchlow SE, Begun J, Pei XY, Jackson SP, Blundell TL et al. (2001). Crystal structure of an Xrcc4-DNA ligase IV complex. Nat Struct Biol 8: 1015–1019.

    CAS  Google Scholar 

  • Sonoda E, Hochegger H, Saberi A, Taniguchi Y, Takeda S . (2006). Differential usage of non-homologous end-joining and homologous recombination in double strand break repair. DNA Repair (Amst) 5: 1021–1029.

    CAS  Google Scholar 

  • Soubeyrand S, Pope L, De Chasseval R, Gosselin D, Dong F, de Villartay JP et al. (2006). Artemis phosphorylated by DNA-dependent protein kinase associates preferentially with discrete regions of chromatin. J Mol Biol 358: 1200–1211.

    CAS  Google Scholar 

  • Soulas-Sprauel P, Le Guyader G, Rivera-Munoz P, Abramowski V, Olivier-Martin C, Goujet-Zalc C et al. (2007). Role for DNA repair factor XRCC4 in immunoglobulin class switch recombination. J Exp Med 204: 1717–1727.

    CAS  Google Scholar 

  • Taccioli GE, Rathbun G, Oltz E, Stamato T, Jeggo PA, Alt FW . (1993). Impairment of V(D)J recombination in double-strand break repair mutants. Science 260: 207–210.

    CAS  Google Scholar 

  • Teo SH, Jackson SP . (1997). Identification of Saccharomyces cerevisiae DNA ligase IV: involvement in DNA double-strand break repair. EMBO J 16: 4788–4795.

    CAS  Google Scholar 

  • Teo SH, Jackson SP . (2000). Lif1p targets the DNA ligase Lig4p to sites of DNA double-strand breaks. Curr Biol 10: 165–168.

    CAS  Google Scholar 

  • Tonegawa S . (1983). Somatic generation of antibody diversity. Nature 302: 575–581.

    CAS  Google Scholar 

  • Tsai CJ, Kim SA, Chu G . (2007). Cernunnos/XLF promotes the ligation of mismatched and noncohesive DNA ends. Proc Natl Acad Sci USA 104: 7851–7856.

    CAS  Google Scholar 

  • Valencia M, Bentele M, Vaze MB, Herrmann G, Kraus E, Lee SE et al. (2001). NEJ1 controls non-homologous end joining in Saccharomyces cerevisiae. Nature 414: 666–669.

    CAS  Google Scholar 

  • van der Burg M, van Veelen LR, Verkaik NS, Wiegant WW, Hartwig NG, Barendregt BH et al. (2006). A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation. J Clin Invest 116: 137–145.

    CAS  Google Scholar 

  • van Overbeek M, de Lange T . (2006). Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase. Curr Biol 16: 1295–1302.

    CAS  Google Scholar 

  • Villa A, Sobacchi C, Notarangelo LD, Bozzi F, Abinun M, Abrahamsen TG et al. (2001). V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood 97: 81–88.

    CAS  Google Scholar 

  • Wang H, Rosidi B, Perrault R, Wang M, Zhang L, Windhofer F et al. (2005a). DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. Cancer Res 65: 4020–4030.

    CAS  Google Scholar 

  • Wang J, Pluth JM, Cooper PK, Cowan MJ, Chen DJ, Yannone SM . (2005b). Artemis deficiency confers a DNA double-strand break repair defect and Artemis phosphorylation status is altered by DNA damage and cell cycle progression. DNA Repair (Amst) 4: 556–570.

    CAS  Google Scholar 

  • Wang M, Wu W, Rosidi B, Zhang L, Wang H, Iliakis G . (2006). PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res 34: 6170–6182.

    CAS  Google Scholar 

  • Ward IM, Reina-San-Martin B, Olaru A, Minn K, Tamada K, Lau JS et al. (2004). 53BP1 is required for class switch recombination. J Cell Biol 165: 459–464.

    CAS  Google Scholar 

  • Weterings E, van Gent DC . (2004). The mechanism of non-homologous end-joining: a synopsis of synapsis. DNA Repair (Amst) 3: 1425–1435.

    CAS  Google Scholar 

  • Wilson TE, Grawunder U, Lieber MR . (1997). Yeast DNA ligase IV mediates non-homologous DNA end joining. Nature 388: 495–498.

    CAS  Google Scholar 

  • Wu PY, Frit P, Malivert L, Revy P, Biard D, Salles B et al. (2007). Interplay between Cernunnos/XLF and NHEJ proteins at DNA ends in the cell. J biol Chem; e-pub ahead of print: 24 August 2007.

  • Wuerffel RA, Du J, Thompson RJ, Kenter AL . (1997). Ig Sgamma3 DNA-specific double strand breaks are induced in mitogen-activated B cells and are implicated in switch recombination. J Immunol 159: 4139–4144.

    CAS  Google Scholar 

  • Wyman C, Kanaar R . (2006). DNA double-strand break repair: all's well that ends well. Annu Rev Genet 40: 363–383.

    CAS  Google Scholar 

  • Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, Murphy M et al. (2007). IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449: 478–483.

    CAS  Google Scholar 

  • Zha S, Alt FW, Cheng HL, Brush JW, Li G . (2007). Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficient murine ES cells. Proc Natl Acad Sci USA 104: 4518–4523.

    CAS  Google Scholar 

  • Zhang X, Succi J, Feng Z, Prithivirajsingh S, Story MD, Legerski RJ . (2004). Artemis is a phosphorylation target of ATM and ATR and is involved in the G2/M DNA damage checkpoint response. Mol Cell Biol 24: 9207–9220.

    CAS  Google Scholar 

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Acknowledgements

Our work was supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), the Agence Nationale de la Recherche (ANR), the Ligue Nationale contre le Cancer (Equipe labellisée LA LIGUE 2005), The Commissariat à l'Energie Atomique (LRC-CEA No40V) and the INCa/Cancéroplole IdF. PR is a scientist from CNRS.

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  1. INSERM, U768, Paris, France

    P Soulas-Sprauel, P Rivera-Munoz, L Malivert, G Le Guyader, V Abramowski, P Revy & J-P de Villartay

  2. Faculté de Médecine René Descartes, Université Paris Descartes, Site Necker, IFR94, Paris, France

    P Soulas-Sprauel, P Rivera-Munoz, L Malivert, G Le Guyader, V Abramowski, P Revy & J-P de Villartay

  3. AP-HP, Hôpital Necker Enfants Malades, Service d'Immunologie et d'Hématologie Pédiatrique, Paris, France

    J-P de Villartay

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  1. P Soulas-Sprauel
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Soulas-Sprauel, P., Rivera-Munoz, P., Malivert, L. et al. V(D)J and immunoglobulin class switch recombinations: a paradigm to study the regulation of DNA end-joining. Oncogene 26, 7780–7791 (2007). https://doi.org/10.1038/sj.onc.1210875

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