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Abnormalities in DNA double-strand break response beyond primary immunodeficiency

  • Progress in Hematology
  • Fanconi anemia and mechanisms of the DNA damage response
  • Published:
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Abstract

V(D)J recombination and class switch recombination are achieved by the cooperative processes of recombination activation gene- or activation-induced cytidine deaminase-dependent DNA cleaving, DNA double-strand break (DSB) response signaling, and DNA repair. Primary immunodeficiency due to dysfunctional DNA recombination can be categorized as severe combined immunodeficiency or other conditions, based on the presence or absence of T cells. We can also classify these diseases as radiosensitive or non-radiosensitive immunodeficiencies. While diseases unable to trigger DNA cleavage do not exhibit radiosensitivity, dysfunction in DSB response signaling or repair does lead to radiosensitive immunodeficiency. Recent studies have begun to clarify the mechanisms underlying the molecular pathogenesis of such DNA DSB-related primary immunodeficiency.

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References

  1. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010;40:179–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Oettinger MA, Schatz DG, Gorka C, Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990;248:1517–22.

    Article  CAS  PubMed  Google Scholar 

  3. Tonegawa S. Somatic generation of antibody diversity. Nature. 1983;302:575–81.

    Article  CAS  PubMed  Google Scholar 

  4. Muramatsu M, Kinoshita K, Fagarasan S, Yamada S, Shinkai Y, Honjo T. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell. 2000;102:553–63.

    Article  CAS  PubMed  Google Scholar 

  5. Petersen-Mahrt SK, Harris RS, Neuberger MS. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature. 2002;418:99–104.

    Article  CAS  PubMed  Google Scholar 

  6. Di Noia J, Neuberger MS. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature. 2002;419:43–8.

    Article  CAS  PubMed  Google Scholar 

  7. Rada C, Williams GT, Nilsen H, Barnes DE, Lindahl T, Neuberger MS. Immunoglobulin isotype switching is inhibited and somatic hypermutation perturbed in UNG-deficient mice. Curr Biol. 2002;12:1748–55.

    Article  CAS  PubMed  Google Scholar 

  8. Imai K, Slupphaug G, Lee W-I, Revy P, Nonoyama S, Catalan N, et al. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol. 2003;4:1023–8.

    Article  CAS  PubMed  Google Scholar 

  9. Guikema JEJ, Linehan EK, Tsuchimoto D, Nakabeppu Y, Strauss PR, Stavnezer J, et al. APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination. J Exp Med. 2007;204:3017–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dickerson SK, Market E, Besmer E, Papavasiliou FN. AID mediates hypermutation by deaminating single stranded DNA. J Exp Med. 2003;197:1291–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pham P, Bransteitter R, Petruska J, Goodman MF. Processive AID-catalysed cytosine deamination on single-stranded DNA simulates somatic hypermutation. Nature. 2003;424:103–7.

    Article  CAS  PubMed  Google Scholar 

  12. Stavnezer J, Guikema JEJ, Schrader CE. Mechanism and regulation of class switch recombination. Annu Rev Immunol. 2008;26:261–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stavnezer J, Schrader CE. Mismatch repair converts AID-instigated nicks to double-strand breaks for antibody class-switch recombination. Trends Genet. 2006;22:23–8.

    Article  CAS  PubMed  Google Scholar 

  14. Schrader CE, Guikema JEJ, Linehan EK, Selsing E, Stavnezer J. Activation-induced cytidine deaminase-dependent DNA breaks in class switch recombination occur during G1 phase of the cell cycle and depend upon mismatch repair. J Immunol. 2007;179:6064–71.

    Article  CAS  PubMed  Google Scholar 

  15. Moshous D, Callebaut I, de Chasseval R, Corneo B, Cavazzana-Calvo M, Le Deist F, et al. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell. 2001;105:177–86.

    Article  CAS  PubMed  Google Scholar 

  16. Ma Y, Pannicke U, Schwarz K, Lieber MR. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell. 2002;108:781–94.

    Article  CAS  PubMed  Google Scholar 

  17. Du L, van Der Burg M, Popov SW, Kotnis A, van Dongen JJM, Gennery AR, et al. Involvement of Artemis in nonhomologous end-joining during immunoglobulin class switch recombination. J Exp Med. 2008;205:3031–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Franco S, Murphy MM, Li G, Borjeson T, Boboila C, Alt FW. DNA-PKcs and Artemis function in the end-joining phase of immunoglobulin heavy chain class switch recombination. J Exp Med. 2008;205:557–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ma Y, Schwarz K, Lieber MR. The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps. DNA Repair. 2005;4(7):845–51.

    Article  CAS  PubMed  Google Scholar 

  20. Lieber MR. The mechanism of human nonhomologous DNA end joining. J Biol Chem. 2008;283:1–5.

    Article  CAS  PubMed  Google Scholar 

  21. Ahnesorg P, Smith P, Jackson SP. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell. 2006;124:301–13.

    Article  CAS  PubMed  Google Scholar 

  22. Buck D, Malivert L, De Chasseval R, Barraud A, Fondanèche MC, Sanal O, et al. Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell. 2006;124:287–99.

    Article  CAS  PubMed  Google Scholar 

  23. Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y. Requirement of the MRN complex for ATM activation by DNA damage. EMBO J. 2003;22:5612–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee J-H, Paull TT. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science. 2005;308:551–4.

    Article  CAS  PubMed  Google Scholar 

  25. Girard P-M, Riballo E, Begg AC, Waugh A, Jeggo PA. Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest. Oncogene. 2002;21:4191–9.

    Article  CAS  PubMed  Google Scholar 

  26. Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273:5858–68.

    Article  CAS  PubMed  Google Scholar 

  27. Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ. ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem. 2001;276:42462–7.

    Article  CAS  PubMed  Google Scholar 

  28. Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C, et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell. 2007;131:887–900.

    Article  CAS  PubMed  Google Scholar 

  29. Huen MSY, Grant R, Manke I, Minn K, Yu X, Yaffe MB, et al. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell. 2007;131:901–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kolas NK, Chapman JR, Nakada S, Ylanko J, Chahwan R, Sweeney FD, et al. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science. 2007;318:1637–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhao GY, Sonoda E, Barber LJ, Oka H, Murakawa Y, Yamada K, et al. A critical role for the ubiquitin-conjugating enzyme Ubc13 in initiating homologous recombination. Mol Cell. 2007;25:663–75.

    Article  CAS  PubMed  Google Scholar 

  32. Bekker-Jensen S, Danielsen JR, Fugger K, Gromova I, Nerstedt A, Bartek J, et al. HERC2 coordinates ubiquitin-dependent assembly of DNA repair factors on damaged chromosomes. Nat Cell Biol. 2009;12:80–6.

    Article  PubMed  Google Scholar 

  33. Stewart GS, Panier S, Townsend K, Al-Hakim AK, Kolas NK, Miller ES, et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell. 2009;136:420–34.

    Article  CAS  PubMed  Google Scholar 

  34. Doil C, Mailand N, Bekker-Jensen S, Menard P, Larsen DH, Pepperkok R, et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell. 2009;136:435–46.

    Article  CAS  PubMed  Google Scholar 

  35. Nakada S, Tai I, Panier S, Al-Hakim A, Iemura S-i, Juang Y-C, et al. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature. 2010;466:941–6.

    Article  CAS  PubMed  Google Scholar 

  36. Wang B, Matsuoka S, Ballif BA, Zhang D, Smogorzewska A, Gygi SP, et al. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science. 2007;316:1194–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sobhian B, Shao G, Lilli DR, Culhane AC, Moreau LA, Xia B, et al. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science. 2007;316:1198–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kim H, Chen J, Yu X. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science. 2007;316:1202–5.

    Article  CAS  PubMed  Google Scholar 

  39. Sato Y, Yoshikawa A, Mimura H, Yamashita M, Yamagata A, Fukai S. Structural basis for specific recognition of Lys 63-linked polyubiquitin chains by tandem UIMs of RAP80. EMBO J. 2009;28:2461–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sanders SL, Portoso M, Mata J, Bähler J, Allshire RC, Kouzarides T. Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage. Cell. 2004;119:603–14.

    Article  CAS  PubMed  Google Scholar 

  41. Nakamura K, Sakai W, Kawamoto T, Bree RT, Lowndes NF, Takeda S, et al. Genetic dissection of vertebrate 53BP1: a major role in non-homologous end joining of DNA double strand breaks. DNA Repair. 2006;5:741–9.

    Article  CAS  PubMed  Google Scholar 

  42. Moynahan ME, Chiu JW, Koller BH, Jasin M, Hill C, Carolina N. Brca1 controls homology-directed DNA repair. Mol Cell. 1999;4:511–8.

    Article  CAS  PubMed  Google Scholar 

  43. Nahas SA, Gatti RA. DNA double strand break repair defects, primary immunodeficiency disorders, and ‘radiosensitivity’. Curr Opin Allergy Clin Immunol. 2009;9:510–6.

    Article  CAS  PubMed  Google Scholar 

  44. Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, et al. RAG mutations in human B cell-negative SCID. Science. 1996;274:97–9.

    Article  CAS  PubMed  Google Scholar 

  45. Revy P, Muto T, Levy Y, Geissmann F, Plebani A, Sanal O, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell. 2000;102:565–75.

    Article  CAS  PubMed  Google Scholar 

  46. Villa A, Santagata S, Bozzi F, Giliani S, Frattini A, Imberti L, et al. Partial V(D)J recombination activity leads to Omenn syndrome. Cell. 1998;93:885–96.

    Article  CAS  PubMed  Google Scholar 

  47. Omenn GS. Familial Reticuloendotheliosis with Eosinophilia. N Engl J Med. 1965;273:427–32.

    Article  CAS  PubMed  Google Scholar 

  48. de Saint-Basile G, Le Deist F, de Villartay JP, Cerf-Bensussan N, Journet O, Brousse N, et al. Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn’s syndrome). J Clin Invest. 1991;87:1352–9.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Péron S, Metin A, Gardès P, Alyanakian M-A, Sheridan E, Kratz CP, et al. Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J Exp Med. 2008;205:2465–72.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Riballo E, Critchlow S, Teo S, Doherty A, Priestley A, Broughton B, et al. Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Curr Biol. 1999;9:699–702.

    Article  CAS  PubMed  Google Scholar 

  51. Ege M, Ma Y, Manfras B, Kalwak K, Lu H, Lieber MR, et al. Omenn syndrome due to ARTEMIS mutations. Blood. 2005;105:4179–86.

    Article  CAS  PubMed  Google Scholar 

  52. Blunt T, Finnie NJ, Taccioli GE, Smith GC, Demengeot J, Gottlieb TM, et al. Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation. Cell. 1995;80:813–23.

    Article  CAS  PubMed  Google Scholar 

  53. Van Der Burg M, IJspeert H, Verkaik NS, Turul T, Wiegant WW, Morotomi-Yano K, et al. A DNA-PKcs mutation in a radiosensitive T-B-SCID patient inhibits Artemis activation and nonhomologous end-joining. J Clin Invest. 2009;119:91–8.

    PubMed  Google Scholar 

  54. Van Der Burg M, Van Veelen LR, Verkaik NS, Wiegant WW, Hartwig NG, Barendregt BH, et al. A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation. J Clin Invest. 2006;116:137–45.

    Article  PubMed  Google Scholar 

  55. O’Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B, et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell. 2001;8:1175–85.

    Article  PubMed  Google Scholar 

  56. van der Burg M, Verkaik NS, Den Dekker AT, Barendregt BH, Pico-Knijnenburg I, Tezcan I, et al. Defective Artemis nuclease is characterized by coding joints with microhomology in long palindromic-nucleotide stretches. Eur J Immunol. 2007;37:3522–8.

    Article  PubMed  Google Scholar 

  57. Yan CT, Boboila C, Souza EK, Franco S, Hickernell TR, Murphy M, et al. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature. 2007;449:478–82.

    Article  CAS  PubMed  Google Scholar 

  58. Li G, Alt FW, Cheng H-L, Brush JW, Goff PH, Murphy MM, et al. Lymphocyte-specific compensation for XLF/cernunnos end-joining functions in V(D)J recombination. Mol Cell. 2008;31:631–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zha S, Guo C, Boboila C, Oksenych V, Cheng H-L, Zhang Y, et al. ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks. Nature. 2010;469:250–4.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Stewart GS, Stankovic T, Byrd PJ, Wechsler T, Miller ES, Huissoon A, et al. RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling. Proc Natl Acad Sci USA. 2007;104:16910–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Li L, Halaby M-J, Hakem A, Cardoso R, El Ghamrasni S, Harding S, et al. Rnf8 deficiency impairs class switch recombination, spermatogenesis, and genomic integrity and predisposes for cancer. J Exp Med. 2010;207:983–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Santos MA, Huen MSY, Jankovic M, Chen H-T, López-Contreras AJ, Klein IA, et al. Class switching and meiotic defects in mice lacking the E3 ubiquitin ligase RNF8. J Exp Med. 2010;207:973–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Manis JP, Morales JC, Xia Z, Kutok JL, Alt FW, Carpenter PB. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat Immunol. 2004;5:481–7.

    Article  CAS  PubMed  Google Scholar 

  64. Difilippantonio S, Gapud E, Wong N, Huang C-Y, Mahowald G, Chen HT, et al. 53BP1 facilitates long-range DNA end-joining during V(D)J recombination. Nature. 2008;456:529–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Dimitrova N, Chen Y-CM, Spector DL, de Lange T. 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility. Nature. 2008;456:524–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM. Immunodeficiency and infections in ataxia-telangiectasia. J Pediatr. 2004;144:505–11.

    Article  PubMed  Google Scholar 

  67. Gregorek H, Chrzanowska KH, Michałkiewicz J, Syczewska M, Madaliński 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. 2002;130:319–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lumsden JM, McCarty T, Petiniot LK, Shen R, Barlow C, Wynn TA, et al. Immunoglobulin class switch recombination is impaired in Atm-deficient mice. J Exp Med. 2004;200:1111–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Reina-San-Martin B, Chen HT, Nussenzweig A, Nussenzweig MC. ATM is required for efficient recombination between immunoglobulin switch regions. J Exp Med. 2004;200:1103–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Reina-San-Martin B, Nussenzweig MC, Nussenzweig A, Difilippantonio S. Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1. Proc Natl Acad Sci USA. 2005;102:1590–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA, et al. Genomic instability in mice lacking histone H2AX. Science. 2002;296:922–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lou Z, Minter-Dykhouse K, Franco S, Gostissa M, Rivera MA, Celeste A, et al. MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol Cell. 2006;21:187–200.

    Article  CAS  PubMed  Google Scholar 

  73. Pan Q, Petit-Frére C, Lähdesmäki A, Gregorek H, Chrzanowska KH, Hammarström L. Alternative end joining during switch recombination in patients with ataxia-telangiectasia. Eur J Immunol. 2002;32:1300–8.

    Article  CAS  PubMed  Google Scholar 

  74. Lähdesmäki A, Taylor AMR, Chrzanowska KH, Pan-Hammarström Q. Delineation of the role of the Mre11 complex in class switch recombination. J Biol Chem. 2004;279:16479–87.

    Article  PubMed  Google Scholar 

  75. Franco S, Gostissa M, Zha S, Lombard DB, Murphy MM, Zarrin AA, et al. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol Cell. 2006;21:201–14.

    Article  CAS  PubMed  Google Scholar 

  76. Ramiro AR, Jankovic M, Callen E, Difilippantonio S, Chen H-T, McBride KM, et al. Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. Nature. 2006;440:105–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bassing CH, Suh H, Ferguson DO, Chua KF, Manis J, Eckersdorff M, et al. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell. 2003;114:359–70.

    Article  CAS  PubMed  Google Scholar 

  78. Tauchi H, Matsuura S, Kobayashi J, Sakamoto S, Komatsu K. Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability. Oncogene. 2002;21:8967–80.

    Article  CAS  PubMed  Google Scholar 

  79. Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI, Jaspers NG, et al. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell. 1999;99:577–87.

    Article  CAS  PubMed  Google Scholar 

  80. Taylora MR, Groom A, Byrd PJ. Ataxia-telangiectasia-like disorder (ATLD)-its clinical presentation and molecular basis. DNA Repair. 2004;3:1219–25.

    Article  Google Scholar 

  81. Waltes R, Kalb R, Gatei M, Kijas AW, Stumm M, Sobeck A, et al. Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder. Am J Hum Genet. 2009;84:605–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work is supported by the Promotion of Environmental Improvement for Independence of Young Researchers “the Kanrinmaru Project” of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan; the Takeda Science Foundation; the Mitsubishi Pharma Research Foundation; the Kanae Research Foundation; and the Sagawa Research Foundation.

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  1. Center of Integrated Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Shinichiro Nakada

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Nakada, S. Abnormalities in DNA double-strand break response beyond primary immunodeficiency. Int J Hematol 93, 425–433 (2011). https://doi.org/10.1007/s12185-011-0836-5

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