|Coordinate||9,972,955 bp (GRCm38)|
|Base Change||T ⇒ C (forward strand)|
|Gene Name||ligase IV, DNA, ATP-dependent|
|Synonym(s)||DNA ligase IV, 5830471N16Rik, tiny|
|Chromosomal Location||9,969,049-9,977,686 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a DNA ligase that joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. This protein is essential for V(D)J recombination and DNA double-strand break (DSB) repair through nonhomologous end joining (NHEJ). This protein forms a complex with the X-ray repair cross complementing protein 4 (XRCC4), and further interacts with the DNA-dependent protein kinase (DNA-PK). Both XRCC4 and DNA-PK are known to be required for NHEJ. The crystal structure of the complex formed by this protein and XRCC4 has been resolved. Defects in this gene are the cause of LIG4 syndrome. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]
PHENOTYPE: Null homozygotes die late in gestation with extensive CNS apoptosis, blocked lymphopoeiesis and failure of V(D)J joining. Carrier fibroblasts show elevated chromosome breaks. ~40% of homozygous hypomorphs survive, with retarded growth, reduced PBL and progressive loss of hematopoietic stem cells. [provided by MGI curators]
|Limits of the Critical Region||9970020 - 9970020 bp|
|Amino Acid Change||Aspartic acid changed to Glycine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000093130] [ENSMUSP00000130807]|
AA Change: D275G
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
AA Change: D275G
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Meta Mutation Damage Score||0.9620|
|Is this an essential gene?||Essential (E-score: 1.000)|
|Phenotypic Category||Autosomal Recessive|
|Candidate Explorer Status||CE: excellent candidate; Verification probability: 0.977; ML prob: 0.992; human score: 1|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2019-12-05 10:44 AM by External Program|
|Record Created||2016-09-14 11:21 PM by Jin Huk Choi|
The posey phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R4763, some of which showed a reduced frequency of B cells (Figure 1), IgD+ B cells (Figure 2), and IgM+ B cells (Figure 3) as well as reduced IgD expression on B cells (Figure 4), all in the peripheral blood. Some mice showed a reduced CD4 to CD8 T cell ratio (Figure 5) due to reduced frequencies of CD4+ T cells in CD3+ T cells (Figure 6), naïve CD4+ T cells in CD4+ T cells (Figure 7), and naïve CD8+ T cells in CD8+ T cells (Figure 8) with concomitant increased frequencies of CD44+ CD8 T cells (Figure 9), CD8+ T cells in CD3+ T cells (Figure 10), central memory CD8+ T cells in CD8+ T cells (Figure 11), effector memory CD4+ T cells in CD4+ T cells (Figure 12). Some mice also showed increased CD44 expression on T cells (Figure 13), CD4 T cells (Figure 14), and CD8+ T cells (Figure 15) in the peripheral blood. Some mice showed increased frequencies of natural killer cells in the peripheral blood (Figure 16). The T-dependent antibody response to ovalbumin administered with aluminum hydroxide was also diminished (Figure 17).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 73 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Lig4: an A to G transition at base pair 9,972,955 (v38) on chromosome 8, or base pair 4,711 in the GenBank genomic region NC_000074 encoding Lig4. The strongest association was found with a recessive model of inheritance to the frequency of effector memory CD4 T cells in CD4 T cells wherein four variant homozygotes departed phenotypically from 12 homozygous reference mice and 10 heterozygous mice with a P value of 3.164 x 10-5 (Figure 18).
The mutation corresponds to residue 1,146 in the mRNA sequence NM_176953 within exon 2 of 2 total exons.
The mutated nucleotide is indicated in red. The mutation results in an aspartic acid (D) to glycine (G) substitution at amino acid 275 (D275G) in the LIG4 protein, and is strongly predicted by PolyPhen-2 to be damaging (score = 1.000).
|Illustration of Mutations in
Gene & Protein
Lig4 encodes DNA ligase IV, a member of the ATP-dependent DNA ligase family. DNA ligase IV has a DNA-binding domain (DBD), a catalytic domain that includes nucleotidyltransferase (NTase) and oligonucleotide binding-fold (OBD) domains, a nuclear localization sequence (NLS), two BRCT domains (BRCT I and BRCT II), and an XRCC4-interacting region (XIR) (Figure 19) (1;2).
The crystal structure of the human DNA ligase IV DBD has been solved [Figure 20; PDB:4HTP; (3) and PDB:3W1B; (4)]. The DBD has two helical subdomains that are connected by two long loops (designated L1 [amino acids 71 to 86] and L2 [amino acids 191 to 201]). Subdomain one is comprised of helices α1, α2, α3, α10, and α11, while subdomain is comprised of helices α4, α5, α6, α7, α8, and α9. The α2 helix interacts with the C-terminal region of Artemis.
Within the catalytic domain, Asp271, Arg278, Arg293, Lys432, Arg443, and Lys449 are ATP-binding sites. Lys273 is the active site, and Asp331 and Asp427 organize magnesium binding. NTase and OBD domains are found in DNA and RNA ligases as well as RNA-capping enzymes (5). The NTase domain engages the nicked DNA strand, and the OBD inserts into the minor groove of the DNA duplex opposite the nick, securing the DNA within the active site of the NTase domain (6).
The BRCT domains mediate protein-protein interactions. BRCT repeats are composed of four central β-sheets surrounded by three α-helices. The BRCT I α2 helix is required for adenovirus-mediated degradation of DNA ligase IV (7). The C-terminal region encompassing the two BRCT domains and the XIR is required for the regulation of the nuclear localization and stability of the DNA ligase IV co-factor XRCC4 as well as binding of the XRCC4/DNA ligase IV complex to chromatin (8-10). Mutations within the BRCT domains (Trp725Arg and Trp893Arg) allow DNA ligase IV binding, but do not allow for the chromatin binding of XRCC4.
Human DNA ligase IV is phosphorylated at Thr650 and putatively at Ser668 or Ser672 (11). DNA ligase IV phosphorylation contributes to its stability, but not to its DNA end joining activity (11). Phosphorylation of mouse DNA ligase IV has not been documented.
The posey mutation results in an aspartic acid (D) to glycine (G) substitution at amino acid 275 (D275G) in DNA ligase IV; amino acid 275 is within the catalytic domain in proximity to two ATP-binding sites and the active site.
LIG4 is ubiquitously expressed (NCBI).
DNA ligase IV is responsible for the ligation step in nonhomologous DNA end joining (NHEJ) (Figure 21) and in V(D)J recombination (Figure 22) (12). In NHEJ, the DNA break is recognized by the Ku heterodimer composed of Ku70 and Ku80, which encircles the DNA and cups the DNA termini into an accessible binding pocket (13). The Ku dimer can recognize blunt ends, hairpin ends, and 5’ or 3’ overhangs; two in vitro studies using purified oligonucleotides containing hairpin ends found that the Ku heterodimer (and DNA-PKCS; see the record for clover) can bind hairpin ends but the kinase could not be activated (14;15). The Ku heterodimer recruits and activates DNA-PKCS, forming the Ku/DNA-PKCS complex known as DNA-PK. The Ku/DNA-PKCS interaction not only assists in localizing the complex to the DNA ends, it also protects DNA ends from nuclease digestion prior to re-ligation (16;17). Following recruitment of DNA-PKCS to the Ku-DNA complex, Ku translocates inward ~10 bp from the DNA ends, allowing DNA-PKCS to bind to the DNA termini (18). Two adjacent DNA-PKCS molecules interact across the DSB, holding the DNA ends in close proximity within a synaptic complex. Crystallographic studies have shown that the synaptic complex in NHEJ consists of two DNA ends, two Ku heterodimers, and two DNA-PKCS proteins (17;19). The formation of a synaptic complex is essential for the activation of DNA-PKCS (17). Nucleases (e.g. 5’: FEN1, EXO1, and Sep1 (20-22); 3’: MRE11 (23)) and polymerases (e.g. polβ, polε, and polδ) are often required to remove several nucleotides or to fill in gaps of several nucleotides, respectively, to facilitate the proper conformation for ligation (24). The colocalization of DNA polymerase X family members (e.g. terminal deoxynucleotidyl transferase (TdT), pol μ, pol λ, and polβ) with DNA-PKCS as well as the interactions of DNA pol X with both Ku and the DNA ligase IV-XRCC4 complex suggest that the DNA polymerase X family participates in the filling in of short gaps prior to re-ligation (25;26). To protect the DNA termini of a DSB from degradation or premature and incorrect ligation, DNA-PKCS is positioned as a “cap” on the DNA ends (27;28). Before re-ligation of the DNA ends and finalization of the DSB repair, the DNA-PKCS cap must be removed or altered. Autophosphorylation of DNA-PKCS results in release of the cap and accessibility of the termini to enzymes and ligases needed to complete the repair (e.g. Artemis, DNA polymerase X family members and the DNA ligase IV-XRCC4 dimer)(17;25;29). Artemis and DNA-PKCS form a complex with endonuclease activity that cleaves 5’ and 3’ overhangs during NHEJ, and opens hairpins generated by the RAG complex during V(D)J recombination [(30); reviewed in (29)]. In order to activate its nuclease activity, Artemis is phosphorylated by DNA-PKCS (31). The DNA ligase IV-XRCC4 dimer rejoins the DNA ends, with XRCC4 both interacting with and catalytically stimulating DNA ligase IV (29). XLF functions to stimulate the ability of XRCC4-DNA ligase IV to ligate in the presence of Mg2+ (32).
During lymphoid cell development, the process of V(D)J recombination generates a variable region exon to which is subsequently joined a constant region gene, together encoding either an immunoglobulin or T cell receptor chain. In V(D)J recombination, a trans-esterification reaction mediated by RAG1/RAG2 produces an excised DNA fragment with blunt signal ends and two covalently closed hairpins at each end of the coding regions that must be joined (16;25). Artemis is essential to opening hairpins for V(D)J recombination following phosphorylation by DNA-PKCS. To process the DNA ends and ligate coding regions, the cell uses the NHEJ pathway. In cells lacking DNA-PKCS, V(D)J recombination intermediates cannot be completely processed and ligated, leading to an accumulation of hairpin intermediates (33). This indicates that DNA-PKCS may be necessary for cleavage of hairpin intermediates as well as for the final end joining step (25).
Mutations in human LIG4 are linked to LIG4 syndrome [alternatively, DNA ligase IV deficiency; OMIM: #606593; (34;35)] and resistance to multiple myeloma [OMIM: #254500; (36)]. Patients with LIG4 syndrome exhibit immunodeficiency as well as delays in development and growth (34). Patients also often display unusual facial features, microcephaly, growth and/or developmental delay, pancytopenia, and various skin abnormalities.
Lig4-deficient mice are embryonic lethal, and the mice exhibited neuronal apoptosis, arrested lymphogenesis, reduced body size, and various cellular defects (37-41). The embryonic lethality, neuronal apoptosis, and fibroblast proliferation/senescence defects observed in the Lig4-deficient mice could be rescued with p53 deficiency; lymphocyte development defects were not rescued (42). K.M. Frank and colleagues propose that most of the phenotypes observed in the Lig4-deficient mice are due to a p53-dependent response to unrepaired DNA damage. The embryonic lethality in the Lig4-deficient mice could also be rescued by deletion of Ku86 (43). Z.E. Karanjawala and colleagues propose that in the case of Lig4 deficiency alone that the lethality phenotype is due the presence of the Artemis:DNA-PKCS nuclease. The loss of Ku86 results in a less severe phenotype, because Ku86 is less efficient than Artemis:DNA-PKCS.
The Arg278His mutation in humans is linked to Lig4 syndrome. Homozygous Lig4R278H/R278H knock-in mice exhibited a reduced life span, reduced body weights compared to wild-type controls, reduced fertility, reduced numbers of B220+ cells in the bone marrow, reduced B220+ IgM+ B cells in the spleen, reduced numbers of CD4-CD8- double negative T cells, CD4+CD8+ double positive T cells, B cells, CD4+ T cells, and CD8+ T cells (44). The Lig4R278H/R278H mice also had reduced IgA, IgG, and IgM in the serum.
Homozygous Lig4 mutant mice (Tyr288Cys) was viable, but showed high levels of endogenous DSBs, immunodeficiency, growth retardation, and reduced brain sizes compared to wild-type mice as well as increased apoptosis in the forebrain, intermediate zone/cortical plate, and ventricular/subventricular zones (45;46). The mice showed impaired V(D)J recombination, B cell class switch recombination, and peripheral lymphocyte survival and proliferation (46). The Tyr288Cys mutant mice also showed a high incidence of thymic tumors.
Homozygous mice (Lig4tiny/tiny) with an ENU-induced mutation exhibited prenatal lethality (born at 40% of the expected frequency), reduced body sizes, reduced B cell numbers, and lack of CD8+ T cells (MGI:3714853 and (47)). Mouse embryonic fibroblasts from the Lig4tiny/tiny mice exhibited reduced ability to repair DNA damage from gamma radiation.
The phenotype of the posey mice indicates loss of LIG4posey function in NHEJ and/or V(D)J recombination.
1) 94°C 2:00
The following sequence of 400 nucleotides is amplified (chromosome 8, - strand):
1 gttgcacaac gtcaccacag atctggaaaa ggtctgcagg cagctgcatg acccctctgt
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
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25. Dip, R., and Naegeli, H. (2005) More than just Strand Breaks: The Recognition of Structural DNA Discontinuities by DNA-Dependent Protein Kinase Catalytic Subunit. FASEB J. 19, 704-715.
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29. Meek, K., Gupta, S., Ramsden, D. A., and Lees-Miller, S. P. (2004) The DNA-Dependent Protein Kinase: The Director at the End. Immunol Rev. 200, 132-141.
30. Ma, Y., Pannicke, U., Schwarz, K., and Lieber, M. R. (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.
31. Jolly, C. J., Cook, A. J., and Manis, J. P. (2008) Fixing DNA Breaks during Class Switch Recombination. J Exp Med. 205, 509-513.
32. Gu, J., Lu, H., Tsai, A. G., Schwarz, K., and Lieber, M. R. (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.
33. Taccioli, G. E., Rathbun, G., Oltz, E., Stamato, T., Jeggo, P. A., and Alt, F. W. (1993) Impairment of V(D)J Recombination in Double-Strand Break Repair Mutants. Science. 260, 207-210.
34. O'Driscoll, M., Cerosaletti, K. M., Girard, P. M., Dai, Y., Stumm, M., Kysela, B., Hirsch, B., Gennery, A., Palmer, S. E., Seidel, J., Gatti, R. A., Varon, R., Oettinger, M. A., Neitzel, H., Jeggo, P. A., and Concannon, P. (2001) DNA Ligase IV Mutations Identified in Patients Exhibiting Developmental Delay and Immunodeficiency. Mol Cell. 8, 1175-1185.
35. 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., and van Gent, D. C. (2006) A New Type of Radiosensitive T-B-NK+ Severe Combined Immunodeficiency Caused by a LIG4 Mutation. J Clin Invest. 116, 137-145.
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38. Gu, Y., Sekiguchi, J., Gao, Y., Dikkes, P., Frank, K., Ferguson, D., Hasty, P., Chun, J., and Alt, F. W. (2000) Defective Embryonic Neurogenesis in Ku-Deficient but Not DNA-Dependent Protein Kinase Catalytic Subunit-Deficient Mice. Proc Natl Acad Sci U S A. 97, 2668-2673.
39. Barnes, D. E., Stamp, G., Rosewell, I., Denzel, A., and Lindahl, T. (1998) Targeted Disruption of the Gene Encoding DNA Ligase IV Leads to Lethality in Embryonic Mice. Curr Biol. 8, 1395-1398.
40. Lee, Y., Barnes, D. E., Lindahl, T., and McKinnon, P. J. (2000) Defective Neurogenesis Resulting from DNA Ligase IV Deficiency Requires Atm. Genes Dev. 14, 2576-2580.
41. Orii, K. E., Lee, Y., Kondo, N., and McKinnon, P. J. (2006) Selective Utilization of Nonhomologous End-Joining and Homologous Recombination DNA Repair Pathways during Nervous System Development. Proc Natl Acad Sci U S A. 103, 10017-10022.
42. Frank, K. M., Sharpless, N. E., Gao, Y., Sekiguchi, J. M., Ferguson, D. O., Zhu, C., Manis, J. P., Horner, J., DePinho, R. A., and Alt, F. W. (2000) DNA Ligase IV Deficiency in Mice Leads to Defective Neurogenesis and Embryonic Lethality Via the p53 Pathway. Mol Cell. 5, 993-1002.
43. Karanjawala, Z. E., Adachi, N., Irvine, R. A., Oh, E. K., Shibata, D., Schwarz, K., Hsieh, C. L., and Lieber, M. R. (2002) 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.
44. Rucci, F., Notarangelo, L. D., Fazeli, A., Patrizi, L., Hickernell, T., Paganini, T., Coakley, K. M., Detre, C., Keszei, M., Walter, J. E., Feldman, L., Cheng, H. L., Poliani, P. L., Wang, J. H., Balter, B. B., Recher, M., Andersson, E. M., Zha, S., Giliani, S., Terhorst, C., Alt, F. W., and Yan, C. T. (2010) Homozygous DNA Ligase IV R278H Mutation in Mice Leads to Leaky SCID and Represents a Model for Human LIG4 Syndrome. Proc Natl Acad Sci U S A. 107, 3024-3029.
45. Gatz, S. A., Ju, L., Gruber, R., Hoffmann, E., Carr, A. M., Wang, Z. Q., Liu, C., and Jeggo, P. A. (2011) Requirement for DNA Ligase IV during Embryonic Neuronal Development. J Neurosci. 31, 10088-10100.
46. Nijnik, A., Dawson, S., Crockford, T. L., Woodbine, L., Visetnoi, S., Bennett, S., Jones, M., Turner, G. D., Jeggo, P. A., Goodnow, C. C., and Cornall, R. J. (2009) Impaired Lymphocyte Development and Antibody Class Switching and Increased Malignancy in a Murine Model of DNA Ligase IV Syndrome. J Clin Invest. 119, 1696-1705.
47. Nijnik, A., Woodbine, L., Marchetti, C., Dawson, S., Lambe, T., Liu, C., Rodrigues, N. P., Crockford, T. L., Cabuy, E., Vindigni, A., Enver, T., Bell, J. I., Slijepcevic, P., Goodnow, C. C., Jeggo, P. A., and Cornall, R. J. (2007) DNA Repair is Limiting for Haematopoietic Stem Cells during Ageing. Nature. 447, 686-690.
|Science Writers||Anne Murray|
|Illustrators||Diantha La Vine|
|Authors||Jin Huk Choi, Xue Zhong, James Butler, Zhao Zhang, Xiaoyu Wang, and Bruce Beutler|