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. 2002 Dec;39(12):900–905. doi: 10.1136/jmg.39.12.900

Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination

P Roddam 1, S Rollinson 1, M O'Driscoll 1, P Jeggo 1, A Jack 1, G Morgan 1
PMCID: PMC1757220  PMID: 12471202

Abstract

The DNA double stranded break (DSB) repair mechanism, non-homologous end joining (NHEJ) represents an essential step in antigen receptor gene rearrangement mechanisms, processes believed to be intimately involved in the aetiology of lymphoproliferative disease. We investigated the potential impact that previously undescribed polymorphisms identified within NHEJ DNA ligase IV (LIG4) have upon predisposition to several lymphoproliferative disorders, including leukaemia, lymphoma, and multiple myeloma. Two LIG4 polymorphisms were examined, both C>T transitions, which result in the amino acid substitutions A3V and T9I. Inheritance of the LIG4 A3V CT genotype was found to be significantly associated with a two-fold reduction in risk of developing multiple myeloma (OR 0.49, 95% CI 0.27 to 0.89). Similarly, inheritance of the LIG4 T9I CT and the T9I TT genotypes were found to associate with a 1.5-fold reduction (OR 0.77, 95% CI 0.51 to 1.17) and a four-fold reduction (OR 0.22, 95% CI 0.07 to 0.70) in risk of developing multiple myeloma respectively, suggesting a gene dosage effect for this polymorphism. The LIG4 A3V and T9I variant alleles are in linkage disequilibrium (D‘=0.95, p<0.0001), and the protective effect associated with these polymorphisms was found to be the result of inheritance of the A3V-T9I CT and A3V-T9I TT haplotypes. These data suggest that genetic variants of NHEJ LIG4 may modulate predisposition to multiple myeloma, a tumour characterised by aberrant immunoglobulin (Ig) class switch recombination.

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Selected References

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  1. Bemark M., Sale J. E., Kim H. J., Berek C., Cosgrove R. A., Neuberger M. S. Somatic hypermutation in the absence of DNA-dependent protein kinase catalytic subunit (DNA-PK(cs)) or recombination-activating gene (RAG)1 activity. J Exp Med. 2000 Nov 20;192(10):1509–1514. doi: 10.1084/jem.192.10.1509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bryans M., Valenzano M. C., Stamato T. D. Absence of DNA ligase IV protein in XR-1 cells: evidence for stabilization by XRCC4. Mutat Res. 1999 Jan 26;433(1):53–58. doi: 10.1016/s0921-8777(98)00063-9. [DOI] [PubMed] [Google Scholar]
  3. Chen L., Trujillo K., Sung P., Tomkinson A. E. Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase. J Biol Chem. 2000 Aug 25;275(34):26196–26205. doi: 10.1074/jbc.M000491200. [DOI] [PubMed] [Google Scholar]
  4. Difilippantonio M. J., Zhu J., Chen H. T., Meffre E., Nussenzweig M. C., Max E. E., Ried T., Nussenzweig A. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature. 2000 Mar 30;404(6777):510–514. doi: 10.1038/35006670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ehrenstein M. R., Rada C., Jones A. M., Milstein C., Neuberger M. S. Switch junction sequences in PMS2-deficient mice reveal a microhomology-mediated mechanism of Ig class switch recombination. Proc Natl Acad Sci U S A. 2001 Nov 20;98(25):14553–14558. doi: 10.1073/pnas.241525998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fenton James A. L., Vaandrager Jan-Willem, Aarts Wilhelmina M., Bende Richard J., Heering Karel, van Dijk Martin, Morgan Gareth, van Noesel Carel J. M., Schuuring Ed, Kluin Philip M. Follicular lymphoma with a novel t(14;18) breakpoint involving the immunoglobulin heavy chain switch mu region indicates an origin from germinal center B cells. Blood. 2002 Jan 15;99(2):716–718. doi: 10.1182/blood.v99.2.716. [DOI] [PubMed] [Google Scholar]
  7. Ferguson D. O., Sekiguchi J. M., Chang S., Frank K. M., Gao Y., DePinho R. A., Alt F. W. The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6630–6633. doi: 10.1073/pnas.110152897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Frank K. M., Sekiguchi J. M., Seidl K. J., Swat W., Rathbun G. A., Cheng H. L., Davidson L., Kangaloo L., Alt F. W. Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature. 1998 Nov 12;396(6707):173–177. doi: 10.1038/24172. [DOI] [PubMed] [Google Scholar]
  9. Gao Y., Ferguson D. O., Xie W., Manis J. P., Sekiguchi J., Frank K. M., Chaudhuri J., Horner J., DePinho R. A., Alt F. W. Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature. 2000 Apr 20;404(6780):897–900. doi: 10.1038/35009138. [DOI] [PubMed] [Google Scholar]
  10. Gennery A. R., Cant A. J., Jeggo P. A. Immunodeficiency associated with DNA repair defects. Clin Exp Immunol. 2000 Jul;121(1):1–7. doi: 10.1046/j.1365-2249.2000.01257.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Grawunder U., Harfst E. How to make ends meet in V(D)J recombination. Curr Opin Immunol. 2001 Apr;13(2):186–194. doi: 10.1016/s0952-7915(00)00203-x. [DOI] [PubMed] [Google Scholar]
  12. Grawunder U., Zimmer D., Fugmann S., Schwarz K., Lieber M. R. DNA ligase IV is essential for V(D)J recombination and DNA double-strand break repair in human precursor lymphocytes. Mol Cell. 1998 Oct;2(4):477–484. doi: 10.1016/s1097-2765(00)80147-1. [DOI] [PubMed] [Google Scholar]
  13. Grawunder U., Zimmer D., Kulesza P., Lieber M. R. Requirement for an interaction of XRCC4 with DNA ligase IV for wild-type V(D)J recombination and DNA double-strand break repair in vivo. J Biol Chem. 1998 Sep 18;273(38):24708–24714. doi: 10.1074/jbc.273.38.24708. [DOI] [PubMed] [Google Scholar]
  14. Grawunder U., Zimmer D., Lieber M. R. DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains. Curr Biol. 1998 Jul 16;8(15):873–876. doi: 10.1016/s0960-9822(07)00349-1. [DOI] [PubMed] [Google Scholar]
  15. Harris N. L., Jaffe E. S., Diebold J., Flandrin G., Muller-Hermelink H. K., Vardiman J., Lister T. A., Bloomfield C. D. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. Ann Oncol. 1999 Dec;10(12):1419–1432. doi: 10.1023/a:1008375931236. [DOI] [PubMed] [Google Scholar]
  16. Junop M. S., Modesti M., Guarné A., Ghirlando R., Gellert M., Yang W. Crystal structure of the Xrcc4 DNA repair protein and implications for end joining. EMBO J. 2000 Nov 15;19(22):5962–5970. doi: 10.1093/emboj/19.22.5962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kanaar R., Hoeijmakers J. H., van Gent D. C. Molecular mechanisms of DNA double strand break repair. Trends Cell Biol. 1998 Dec;8(12):483–489. doi: 10.1016/s0962-8924(98)01383-x. [DOI] [PubMed] [Google Scholar]
  18. Kinoshita K., Honjo T. Linking class-switch recombination with somatic hypermutation. Nat Rev Mol Cell Biol. 2001 Jul;2(7):493–503. doi: 10.1038/35080033. [DOI] [PubMed] [Google Scholar]
  19. Küppers R., Dalla-Favera R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene. 2001 Sep 10;20(40):5580–5594. doi: 10.1038/sj.onc.1204640. [DOI] [PubMed] [Google Scholar]
  20. Manis J. P., Gu Y., Lansford R., Sonoda E., Ferrini R., Davidson L., Rajewsky K., Alt F. W. Ku70 is required for late B cell development and immunoglobulin heavy chain class switching. J Exp Med. 1998 Jun 15;187(12):2081–2089. doi: 10.1084/jem.187.12.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Modesti M., Hesse J. E., Gellert M. DNA binding of Xrcc4 protein is associated with V(D)J recombination but not with stimulation of DNA ligase IV activity. EMBO J. 1999 Apr 1;18(7):2008–2018. doi: 10.1093/emboj/18.7.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. O'Driscoll M., Cerosaletti K. M., Girard P. M., Dai Y., Stumm M., Kysela B., Hirsch B., Gennery A., Palmer S. E., Seidel J. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell. 2001 Dec;8(6):1175–1185. doi: 10.1016/s1097-2765(01)00408-7. [DOI] [PubMed] [Google Scholar]
  23. Papavasiliou F., Casellas R., Suh H., Qin X. F., Besmer E., Pelanda R., Nemazee D., Rajewsky K., Nussenzweig M. C. V(D)J recombination in mature B cells: a mechanism for altering antibody responses. Science. 1997 Oct 10;278(5336):298–301. doi: 10.1126/science.278.5336.298. [DOI] [PubMed] [Google Scholar]
  24. Riballo E., Critchlow S. E., Teo S. H., Doherty A. J., Priestley A., Broughton B., Kysela B., Beamish H., Plowman N., Arlett C. F. Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Curr Biol. 1999 Jul 1;9(13):699–702. doi: 10.1016/s0960-9822(99)80311-x. [DOI] [PubMed] [Google Scholar]
  25. Roddam P. L., Rollinson S., Kane E., Roman E., Moorman A., Cartwright R., Morgan G. J. Poor metabolizers at the cytochrome P450 2D6 and 2C19 loci are at increased risk of developing adult acute leukaemia. Pharmacogenetics. 2000 Oct;10(7):605–615. doi: 10.1097/00008571-200010000-00004. [DOI] [PubMed] [Google Scholar]
  26. Roth D. B., Gellert M. New guardians of the genome. Nature. 2000 Apr 20;404(6780):823–825. doi: 10.1038/35009180. [DOI] [PubMed] [Google Scholar]
  27. Sekiguchi J., Ferguson D. O., Chen H. T., Yang E. M., Earle J., Frank K., Whitlow S., Gu Y., Xu Y., Nussenzweig A. Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development. Proc Natl Acad Sci U S A. 2001 Mar 6;98(6):3243–3248. doi: 10.1073/pnas.051632098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Singleton B. K., Priestley A., Steingrimsdottir H., Gell D., Blunt T., Jackson S. P., Lehmann A. R., Jeggo P. A. Molecular and biochemical characterization of xrs mutants defective in Ku80. Mol Cell Biol. 1997 Mar;17(3):1264–1273. doi: 10.1128/mcb.17.3.1264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Storb U., Shen H. M., Michael N., Kim N. Somatic hypermutation of immunoglobulin and non-immunoglobulin genes. Philos Trans R Soc Lond B Biol Sci. 2001 Jan 29;356(1405):13–19. doi: 10.1098/rstb.2000.0743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Taccioli G. E., Amatucci A. G., Beamish H. J., Gell D., Xiang X. H., Torres Arzayus M. I., Priestley A., Jackson S. P., Marshak Rothstein A., Jeggo P. A. Targeted disruption of the catalytic subunit of the DNA-PK gene in mice confers severe combined immunodeficiency and radiosensitivity. Immunity. 1998 Sep;9(3):355–366. doi: 10.1016/s1074-7613(00)80618-4. [DOI] [PubMed] [Google Scholar]
  31. Vaandrager J. W., Schuuring E., Philippo K., Kluin P. M. V(D)J recombinase-mediated transposition of the BCL2 gene to the IGH locus in follicular lymphoma. Blood. 2000 Sep 1;96(5):1947–1952. [PubMed] [Google Scholar]
  32. Vanasse G. J., Concannon P., Willerford D. M. Regulated genomic instability and neoplasia in the lymphoid lineage. Blood. 1999 Dec 15;94(12):3997–4010. [PubMed] [Google Scholar]
  33. van Gent D. C., Hoeijmakers J. H., Kanaar R. Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet. 2001 Mar;2(3):196–206. doi: 10.1038/35056049. [DOI] [PubMed] [Google Scholar]

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