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Gene Review

LIG4  -  ligase IV, DNA, ATP-dependent

Homo sapiens

Synonyms: DNA ligase 4, DNA ligase IV
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Disease relevance of LIG4

  • A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation [1].
  • To date, LIG4 mutations have only been described in a radiosensitive leukemia patient and in 4 patients with a designated LIG4 syndrome, which is associated with chromosomal instability, pancytopenia, and developmental and growth delay [1].
  • In the non-homologous end-joining (NHEJ) pathway, a polymorphism in LIG4 (T>C at nt 1977) was associated with a decrease in breast cancer risk [P=0.09; OR CC versus TT=0.7 (0.4-1.0)] [2].
  • 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) [3].
  • In addition, deletion of one or both copies of LIG4 resulted in attenuation of virulence in a murine model of candidiasis [4].

High impact information on LIG4

  • XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining [5].
  • Specific stimulation of DNA ligase IV-mediated end-joining by Mre11 complexes from S. cerevisiae suggests the possibility of a direct role in nonhomologous end-joining in eukaryotic cells [6].
  • The mutant phenotypes are consistent with functions of LIG4 in an illegitimate DNA end-joining pathway and ensuring efficient meiosis [7].
  • In contrast, lig4 mutant cells have a 1000-fold reduced capacity for correct recircularization of linearized plasmids by illegitimate end-joining after transformation [7].
  • Moreover, homozygous lig4 mutant diploids sporulate less efficiently than isogenic wild-type cells, and show retarded progression through meiotic prophase I [7].

Biological context of LIG4

  • Unlike CDC9, LIG4 is not essential for DNA replication, RAD52-dependent homologous recombination nor the repair of UV light-induced DNA damage [8].
  • Interestingly, these phenotypes were significantly suppressed by deletion of LIG4, suggesting that nonhomologous end-joining (NHEJ) is unfavorable for integrity and survival of cells lacking BLM [9].
  • Most of transcripts involved in DNA repair were not detected but repression of POLD1 in the adult group and induction of XRCC5 and LIG4 were observed after UVA irradiation, as a function of age [10].
  • Two LIG4 polymorphisms were examined, both C>T transitions, which result in the amino acid substitutions A3V and T9I [3].
  • 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 [3].

Anatomical context of LIG4

  • The LIG4-deficient SCID patient had an incomplete but severe block in precursor B cell differentiation, resulting in extremely low levels of blood B cells [1].
  • The LIG4-defective cell lines also showed impaired end joining in an in vitro assay using cell-free extracts [11].
  • These observations contrast with the severity of the clinical immunodeficiency, suggesting that Lig4 may have additional critical roles in lymphocyte survival beyond V(D)J recombination [12].
  • Residual activity of Lig4 in these patients is underscored by a normal pattern of TCR-alpha and -beta junctions in the T cells of the patients and a moderate impairment of V(D)J recombination as tested in vitro [12].
  • An in vivo plasmid assay shows that DNA ligase IV-deficient mouse embryo fibroblasts retain significant DNA end joining activity that can be reduced by up to 80% by knocking down DNA ligase III using RNA interference [13].

Associations of LIG4 with chemical compounds

  • At 0.5 mM Mg(2+), where only DNA ligase IV is expected to retain activity, low levels of end joining ( approximately 10% of 10 mM) were seen in the control but there was no detectable activity in 180BR cells [14].
  • Substitution of these amino acids with alanine, individually or in combination, led to changes in Lig4 protein stability of mouse Lig4 [15].
  • The inserted sequence had no sequence identity with other eukaryotic counterparts of DNA ligase IV or with another aspartic acid and glutamic acid rich sequence inserted in C. cinereus proliferating cell nuclear antigen (CcPCNA), although the length and the percentages of aspartic and glutamic acids were similar [16].

Physical interactions of LIG4

  • Here we show that DNA ligase IV co-immunoprecipitates with XRCC4 and that these two proteins specifically interact with one another in a yeast two-hybrid system [17].
  • Using immunoaffinity purification or purified proteins, we show that AHNAK interacts specifically with the DNA ligase IV-XRCC4 complex, a complex that functions in DNA non-homologous end-joining [18].

Regulatory relationships of LIG4


Other interactions of LIG4

  • These data provide some evidence that variants in XRCC2 and LIG4 alter breast cancer risk, together with stronger evidence that variants of XRCC3 are associated with risk [2].
  • Three mammalian genes encoding DNA ligases, LIG1, LIG3 and LIG4, have been identified [21].
  • A fourth DNA ligase (DNA ligase IV) has been purified from human cells and shown to be identical to the 96-kDa DNA ligase by unique agreement between mass spectrometry data on tryptic peptides from the purified enzyme and the predicted open reading frame of the cloned cDNA [22].
  • In the presence of DNA-PK, the majority of the joining events catalyzed by DNA ligase IV-XRCC4 were intermolecular because Ku inhibited intramolecular ligation, but DNA-PKcs still stimulated intramolecular ligation [19].
  • More intriguingly, however, these experiments revealed the presence of an alternative, DNA ligase IV-independent end-joining pathway, which was significantly affected by the loss of BLM [9].

Analytical, diagnostic and therapeutic context of LIG4

  • Because nonhomologous integration is eliminated in a LIG4-disrupted strain, integration occurs only at the targeted site in mus-53 mutants, making them an extremely efficient and safe host for gene targeting [23].
  • Molecular cloning and expression of human cDNAs encoding a novel DNA ligase IV and DNA ligase III, an enzyme active in DNA repair and recombination [22].
  • Cells with hypomorphic mutations in DNA ligase IV exhibit a substantial repair defect up to 24 h after treatment but continue to repair for several days and finally reach a level of unrepaired DSBs similar to that of wild-type cells [24].
  • We previously reported a homozygous mutation (R278H) in DNA ligase IV in a developmentally normal leukemia patient who overresponded to radiotherapy [25].
  • Co-immunoprecipitation and adenylylation assays demonstrated that this associated factor was the recently identified human DNA ligase IV [26].


  1. A new type of radiosensitive T-B-NK+ severe combined immunodeficiency caused by a LIG4 mutation. van der Burg, M., van Veelen, L.R., Verkaik, N.S., Wiegant, W.W., Hartwig, N.G., Barendregt, B.H., Brugmans, L., Raams, A., Jaspers, N.G., Zdzienicka, M.Z., van Dongen, J.J., van Gent, D.C. J. Clin. Invest. (2006) [Pubmed]
  2. Variants in DNA double-strand break repair genes and breast cancer susceptibility. Kuschel, B., Auranen, A., McBride, S., Novik, K.L., Antoniou, A., Lipscombe, J.M., Day, N.E., Easton, D.F., Ponder, B.A., Pharoah, P.D., Dunning, A. Hum. Mol. Genet. (2002) [Pubmed]
  3. Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination. Roddam, P.L., Rollinson, S., O'Driscoll, M., Jeggo, P.A., Jack, A., Morgan, G.J. J. Med. Genet. (2002) [Pubmed]
  4. Phenotypic analysis and virulence of Candida albicans LIG4 mutants. Andaluz, E., Calderone, R., Reyes, G., Larriba, G. Infect. Immun. (2001) [Pubmed]
  5. XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Ahnesorg, P., Smith, P., Jackson, S.P. Cell (2006) [Pubmed]
  6. New glimpses of an old machine. Paull, T.T. Cell (2001) [Pubmed]
  7. A newly identified DNA ligase of Saccharomyces cerevisiae involved in RAD52-independent repair of DNA double-strand breaks. Schär, P., Herrmann, G., Daly, G., Lindahl, T. Genes Dev. (1997) [Pubmed]
  8. Identification of Saccharomyces cerevisiae DNA ligase IV: involvement in DNA double-strand break repair. Teo, S.H., Jackson, S.P. EMBO J. (1997) [Pubmed]
  9. Genetic interactions between BLM and DNA ligase IV in human cells. So, S., Adachi, N., Lieber, M.R., Koyama, H. J. Biol. Chem. (2004) [Pubmed]
  10. Ageing effects on the expression of cell defence genes after UVA irradiation in human male cutaneous fibroblasts using cDNA arrays. Hazane, F., Valenti, K., Sauvaigo, S., Peinnequin, A., Mouret, C., Favier, A., Beani, J.C. J. Photochem. Photobiol. B, Biol. (2005) [Pubmed]
  11. Impact of DNA ligase IV on the fidelity of end joining in human cells. Smith, J., Riballo, E., Kysela, B., Baldeyron, C., Manolis, K., Masson, C., Lieber, M.R., Papadopoulo, D., Jeggo, P. Nucleic Acids Res. (2003) [Pubmed]
  12. Severe combined immunodeficiency and microcephaly in siblings with hypomorphic mutations in DNA ligase IV. Buck, D., Moshous, D., de Chasseval, R., Ma, Y., le Deist, F., Cavazzana-Calvo, M., Fischer, A., Casanova, J.L., Lieber, M.R., de Villartay, J.P. Eur. J. Immunol. (2006) [Pubmed]
  13. DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. Wang, H., Rosidi, B., Perrault, R., Wang, M., Zhang, L., Windhofer, F., Iliakis, G. Cancer Res. (2005) [Pubmed]
  14. Genetic evidence for the involvement of DNA ligase IV in the DNA-PK-dependent pathway of non-homologous end joining in mammalian cells. Wang, H., Zeng, Z.C., Perrault, A.R., Cheng, X., Qin, W., Iliakis, G. Nucleic Acids Res. (2001) [Pubmed]
  15. Phosphorylation and regulation of DNA ligase IV stability by DNA-dependent protein kinase. Wang, Y.G., Nnakwe, C., Lane, W.S., Modesti, M., Frank, K.M. J. Biol. Chem. (2004) [Pubmed]
  16. DNA ligase IV from a basidiomycete, Coprinus cinereus, and its expression during meiosis. Namekawa, S., Ichijima, Y., Hamada, F., Kasai, N., Iwabata, K., Nara, T., Teraoka, H., Sugawara, F., Sakaguchi, K. Microbiology (Reading, Engl.) (2003) [Pubmed]
  17. Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells. Grawunder, U., Wilm, M., Wu, X., Kulesza, P., Wilson, T.E., Mann, M., Lieber, M.R. Nature (1997) [Pubmed]
  18. AHNAK interacts with the DNA ligase IV-XRCC4 complex and stimulates DNA ligase IV-mediated double-stranded ligation. Stiff, T., Shtivelman, E., Jeggo, P., Kysela, B. DNA Repair (Amst.) (2004) [Pubmed]
  19. Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase. Chen, L., Trujillo, K., Sung, P., Tomkinson, A.E. J. Biol. Chem. (2000) [Pubmed]
  20. Non-histone chromosomal proteins HMG1 and 2 enhance ligation reaction of DNA double-strand breaks. Nagaki, S., Yamamoto, M., Yumoto, Y., Shirakawa, H., Yoshida, M., Teraoka, H. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  21. Mammalian DNA ligases. Tomkinson, A.E., Levin, D.S. Bioessays (1997) [Pubmed]
  22. Molecular cloning and expression of human cDNAs encoding a novel DNA ligase IV and DNA ligase III, an enzyme active in DNA repair and recombination. Wei, Y.F., Robins, P., Carter, K., Caldecott, K., Pappin, D.J., Yu, G.L., Wang, R.P., Shell, B.K., Nash, R.A., Schär, P. Mol. Cell. Biol. (1995) [Pubmed]
  23. Nonhomologous chromosomal integration of foreign DNA is completely dependent on MUS-53 (human Lig4 homolog) in Neurospora. Ishibashi, K., Suzuki, K., Ando, Y., Takakura, C., Inoue, H. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  24. A double-strand break repair defect in ATM-deficient cells contributes to radiosensitivity. Kühne, M., Riballo, E., Rief, N., Rothkamm, K., Jeggo, P.A., Löbrich, M. Cancer Res. (2004) [Pubmed]
  25. Cellular and biochemical impact of a mutation in DNA ligase IV conferring clinical radiosensitivity. Riballo, E., Doherty, A.J., Dai, Y., Stiff, T., Oettinger, M.A., Jeggo, P.A., Kysela, B. J. Biol. Chem. (2001) [Pubmed]
  26. Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV. Critchlow, S.E., Bowater, R.P., Jackson, S.P. Curr. Biol. (1997) [Pubmed]
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