Gene Symbol: Lig4
Description: ligase IV, DNA, ATP-dependent
Alias: 5830471N16Rik, tiny, DNA ligase 4, DNA ligase IV, polydeoxyribonucleotide synthase [ATP] 4
Species: mouse
Products:     Lig4

Top Publications

  1. Mills K, Ferguson D, Alt F. The role of DNA breaks in genomic instability and tumorigenesis. Immunol Rev. 2003;194:77-95 pubmed
    ..Here, we review the current thinking about DSBs and DSBR in chromosomal instability and tumorigenesis, and we highlight the implications for understanding the karyotypic features associated with human tumors. ..
  2. Barnes D, Stamp G, Rosewell I, Denzel A, Lindahl T. Targeted disruption of the gene encoding DNA ligase IV leads to lethality in embryonic mice. Curr Biol. 1998;8:1395-8 pubmed
    b>DNA ligase IV is the most recently identified member of a family of enzymes joining DNA strand breaks in mammalian cell nuclei [1] [2]...
  3. Karanjawala Z, Adachi N, Irvine R, Oh E, Shibata D, Schwarz K, et al. 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). 2002;1:1017-26 pubmed
    ..Ku mutants have an intermediate severity with accelerated senescence. The XRCC4 and DNA ligase IV mutants are the most severe, resulting in embryonic lethality...
  4. Van Nguyen T, Puebla Osorio N, Pang H, Dujka M, Zhu C. DNA damage-induced cellular senescence is sufficient to suppress tumorigenesis: a mouse model. J Exp Med. 2007;204:1453-61 pubmed
  5. Lee Y, McKinnon P. DNA ligase IV suppresses medulloblastoma formation. Cancer Res. 2002;62:6395-9 pubmed
    Substantial neural defects are often present in mice with targeted inactivation of DNA repair factors such as DNA ligase IV (Lig4)...
  6. Lee Y, Barnes D, Lindahl T, McKinnon P. Defective neurogenesis resulting from DNA ligase IV deficiency requires Atm. Genes Dev. 2000;14:2576-80 pubmed
    ..Inactivation of certain DNA repair genes such as DNA ligase IV results in massive neuronal apoptosis and embryonic lethality in the mouse, indicating the occurrence of ..
  7. Frappart P, Lee Y, Russell H, Chalhoub N, Wang Y, Orii K, et al. Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency. Proc Natl Acad Sci U S A. 2009;106:1880-5 pubmed publisher
    ..Here, we inactivated DNA double-strand break repair (DSBR) proteins, DNA Ligase IV (Lig4), Xrcc2, and Brca2, or combined Lig4/Xrcc2 during neural development using Nestin-cre...
  8. Gao Y, Katyal S, Lee Y, Zhao J, Rehg J, Russell H, et al. DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair. Nature. 2011;471:240-4 pubmed publisher in mammalian cells involves three distinct DNA ligases: ligase I (Lig1), ligase III (Lig3) and ligase IV (Lig4)...
  9. Shull E, Lee Y, Nakane H, Stracker T, Zhao J, Russell H, et al. Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS. Genes Dev. 2009;23:171-80 pubmed publisher
    ..We found a pronounced resistance to DNA damage-induced apoptosis after ionizing radiation or DNA ligase IV (Lig4) loss in the Mre11(ATLD1/ATLD1) nervous system that was associated with defective Atm activation and ..

More Information


  1. Zhu C, Mills K, Ferguson D, Lee C, Manis J, Fleming J, et al. Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell. 2002;109:811-21 pubmed
    ..This recombination event employs a microhomology-based end-joining repair pathway, as opposed to classic NHEJ or homologous recombination. These findings suggest a general model for oncogenic complicon formation. ..
  2. Mills K, Ferguson D, Essers J, Eckersdorff M, Kanaar R, Alt F. Rad54 and DNA Ligase IV cooperate to maintain mammalian chromatid stability. Genes Dev. 2004;18:1283-92 pubmed
    ..relationship between HR and NHEJ modes of DSB repair, we generated cells doubly deficient for the NHEJ factor DNA Ligase IV (Lig4) and the HR factor Rad54...
  3. Boboila C, Jankovic M, Yan C, Wang J, Wesemann D, Zhang T, et al. Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70. Proc Natl Acad Sci U S A. 2010;107:3034-9 pubmed publisher
    ..classical nonhomologous end-joining (C-NHEJ), which employs the Ku70/80 complex for DSB recognition and XRCC4/DNA ligase 4 for ligation...
  4. Orii K, Lee Y, Kondo N, McKinnon P. Selective utilization of nonhomologous end-joining and homologous recombination DNA repair pathways during nervous system development. Proc Natl Acad Sci U S A. 2006;103:10017-22 pubmed
    ..of HR (Xrcc2 deficiency) only occurred in proliferating neural precursor cells, whereas disruption of NHEJ (DNA ligase IV deficiency) mainly affected differentiating cells at later developmental stages...
  5. Windhofer F, Wu W, Iliakis G. Low levels of DNA ligases III and IV sufficient for effective NHEJ. J Cell Physiol. 2007;213:475-83 pubmed
    ..While D-NHEJ relies exclusively on DNA ligase IV, recent work points to DNA ligase III as a component of B-NHEJ...
  6. Frank K, Sekiguchi J, Seidl K, Swat W, Rathbun G, Cheng H, et al. Late embryonic lethality and impaired V(D)J recombination in mice lacking DNA ligase IV. Nature. 1998;396:173-7 pubmed
    ..The precise function of XRCC4 is unknown, but it interacts with DNA ligase IV. Ligase IV is one of the three known mammalian DNA ligases; however, the in vivo functions of these ligases ..
  7. Han L, Yu K. Altered kinetics of nonhomologous end joining and class switch recombination in ligase IV-deficient B cells. J Exp Med. 2008;205:2745-53 pubmed publisher
    ..By somatic gene targeting of DNA ligase IV (Lig4; a key component of NHEJ) in a B cell line (CH12F3) capable of highly efficient CSR in vitro, we found ..
  8. Yan C, Boboila C, Souza E, Franco S, Hickernell T, Murphy M, et al. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature. 2007;449:478-82 pubmed
    ..CSR joins also display direct and microhomology joins, and CSR has been suggested to use C-NHEJ. Xrcc4 and DNA ligase IV (Lig4), which cooperatively catalyse the ligation step of C-NHEJ, are the most specific C-NHEJ factors; they ..
  9. Bentley D, Harrison C, Ketchen A, Redhead N, Samuel K, Waterfall M, et al. DNA ligase I null mouse cells show normal DNA repair activity but altered DNA replication and reduced genome stability. J Cell Sci. 2002;115:1551-61 pubmed
  10. Frank K, Sharpless N, Gao Y, Sekiguchi J, Ferguson D, Zhu C, et al. DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol Cell. 2000;5:993-1002 pubmed
    b>DNA ligase IV (LIG4) is a nonhomologous end-joining (NHEJ) protein used for V(D)J recombination and DNA repair...
  11. Gao Y, Sun Y, Frank K, Dikkes P, Fujiwara Y, Seidl K, et al. A critical role for DNA end-joining proteins in both lymphogenesis and neurogenesis. Cell. 1998;95:891-902 pubmed
    ..We find similar neuronal developmental defects in embryos that lack DNA ligase IV, an XRCC4-associated protein...
  12. Sfeir A, Kosiyatrakul S, Hockemeyer D, MacRae S, Karlseder J, Schildkraut C, et al. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell. 2009;138:90-103 pubmed publisher
    ..These results identify a second telomere replication problem that is solved by the shelterin component TRF1. ..
  13. Nijnik A, Dawson S, Crockford T, Woodbine L, Visetnoi S, Bennett S, et al. Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome. J Clin Invest. 2009;119:1696-705 pubmed publisher
    Hypomorphic mutations in DNA ligase IV (LIG4) cause a human syndrome of immunodeficiency, radiosensitivity, and growth retardation due to defective DNA repair by the nonhomologous end-joining (NHEJ) pathway...
  14. Green M, Monti S, Dalla Favera R, Pasqualucci L, Walsh N, Schmidt Supprian M, et al. Signatures of murine B-cell development implicate Yy1 as a regulator of the germinal center-specific program. Proc Natl Acad Sci U S A. 2011;108:2873-8 pubmed publisher
    ..These findings offer important tools and insights for elucidating differences between normal and malignant B cells. ..
  15. Wang X, Chan K, Ming X, Lui V, Poon R, Lo C, et al. G1 checkpoint establishment in vivo during embryonic liver development. BMC Dev Biol. 2014;14:23 pubmed publisher
    ..Our study is the first to demonstrate the establishment of the DNA damage-mediated G1 cell cycle checkpoint in liver cells during embryogenesis and its in vivo biological effects during embryonic liver development. ..
  16. Maruyama T, Dougan S, Truttmann M, Bilate A, Ingram J, Ploegh H. Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining. Nat Biotechnol. 2015;33:538-42 pubmed publisher
    ..To promote HDR at the expense of NHEJ, we targeted DNA ligase IV, a key enzyme in the NHEJ pathway, using the inhibitor Scr7...
  17. Dooley J, Tian L, Schonefeldt S, Delghingaro Augusto V, Garcia Perez J, Pasciuto E, et al. Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes. Nat Genet. 2016;48:519-27 pubmed publisher
    ..The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes. ..
  18. Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature. 2007;447:686-90 pubmed
    ..Here we address this question by taking advantage of the highly specific role of DNA ligase IV in the repair of DNA double-strand breaks by non-homologous end-joining, and by the discovery of a unique ..
  19. Boboila C, Yan C, Wesemann D, Jankovic M, Wang J, Manis J, et al. Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4. J Exp Med. 2010;207:417-27 pubmed publisher
    ..DNA double-strand break (DSB) repair pathway employs the Ku70/80 complex (Ku) for DSB recognition and the XRCC4/DNA ligase 4 (Lig4) complex for ligation...
  20. Shimada M, Dumitrache L, Russell H, McKinnon P. Polynucleotide kinase-phosphatase enables neurogenesis via multiple DNA repair pathways to maintain genome stability. EMBO J. 2015;34:2465-80 pubmed publisher
    ..These data illuminate the basis for selective neural vulnerability in DNA repair deficiency disease. ..
  21. Costantini S, Woodbine L, Andreoli L, Jeggo P, Vindigni A. Interaction of the Ku heterodimer with the DNA ligase IV/Xrcc4 complex and its regulation by DNA-PK. DNA Repair (Amst). 2007;6:712-22 pubmed
    ..we characterize the interaction between two key components of the NHEJ machinery, the Ku heterodimer and the DNA ligase IV/Xrcc4 complex...
  22. Rommel P, Bosque D, Gitlin A, Croft G, Heintz N, Casellas R, et al. Fate mapping for activation-induced cytidine deaminase (AID) marks non-lymphoid cells during mouse development. PLoS ONE. 2013;8:e69208 pubmed publisher
    ..Finally, in the adult mouse brain, AID(cre) marks a small fraction of diverse neurons and distinct neuronal populations, including pyramidal cells in cortical layer IV. ..
  23. Cohen Z, Bacharach E, Lavi S. Mouse major satellite DNA is prone to eccDNA formation via DNA Ligase IV-dependent pathway. Oncogene. 2006;25:4515-24 pubmed
    ..Using siRNA technique we show that DNA Ligase IV is engaged in ECMS synthesis...
  24. Pierce A, Jasin M. NHEJ deficiency and disease. Mol Cell. 2001;8:1160-1 pubmed
    In mouse and human, diseases associated with deficiency of DNA ligase IV, a protein involved in DNA double-strand break repair, have been identified...
  25. Boboila C, Oksenych V, Gostissa M, Wang J, Zha S, Zhang Y, et al. Robust chromosomal DNA repair via alternative end-joining in the absence of X-ray repair cross-complementing protein 1 (XRCC1). Proc Natl Acad Sci U S A. 2012;109:2473-8 pubmed publisher
    ..However, in B cells deficient for one or more requisite C-NHEJ factors, such as DNA ligase 4 (Lig4) or XRCC4, end-joining during CSR occurs by a distinct alternative end-joining (A-EJ) pathway...
  26. Han L, Mao W, Yu K. X-ray repair cross-complementing protein 1 (XRCC1) deficiency enhances class switch recombination and is permissive for alternative end joining. Proc Natl Acad Sci U S A. 2012;109:4604-8 pubmed publisher
    ..Here we demonstrate that XRCC1 deficiency slightly increases the efficiency of CSR. More importantly, Lig4 and XRCC1 double-deficient cells switch as efficiently as Lig4-deficient cells, clearly indicating that XRCC1 is ..
  27. Lee Y, Katyal S, Downing S, Zhao J, Russell H, McKinnon P. Neurogenesis requires TopBP1 to prevent catastrophic replicative DNA damage in early progenitors. Nat Neurosci. 2012;15:819-26 pubmed publisher
    ..Thus, TopBP1 is crucial for maintaining genome integrity in the early progenitors that drive neurogenesis. ..
  28. Vats K, Ishwad C, Singla I, Vats A, Ferrell R, Ellis D, et al. A locus for renal malformations including vesico-ureteric reflux on chromosome 13q33-34. J Am Soc Nephrol. 2006;17:1158-67 pubmed
    ..Herein is reported a new locus on chromosome 13q33q34 that can be associated with VUR with several genes showing mRNA expression patterns that suggest their potential for involvement in renal/urinary tract developmental anomalies...
  29. Ferguson D, Sekiguchi J, Chang S, Frank K, Gao Y, DePinho R, et al. 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;97:6630-3 pubmed
    ..MEFs homozygous for mutations that inactivate either DNA ligase IV (Lig4) or Ku70 display dramatic genomic instability, even in the absence of exogenous DNA damaging agents...
  30. Sekiguchi J, Ferguson D, Chen H, Yang E, Earle J, Frank K, et al. Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development. Proc Natl Acad Sci U S A. 2001;98:3243-8 pubmed
    b>DNA ligase IV (Lig4) and the DNA-dependent protein kinase (DNA-PK) function in nonhomologous end joining (NHEJ)...
  31. Lottersberger F, Bothmer A, Robbiani D, Nussenzweig M, de Lange T. Role of 53BP1 oligomerization in regulating double-strand break repair. Proc Natl Acad Sci U S A. 2013;110:2146-51 pubmed publisher
    ..Second, 53BP1-dependent repression of CtIP at double-strand breaks (DSBs) is unlikely to be sufficient for the generation of radial chromosomes in PARP1 inhibitor-treated Brca1-deficient cells. ..
  32. Barazzuol L, Rickett N, Ju L, Jeggo P. Low levels of endogenous or X-ray-induced DNA double-strand breaks activate apoptosis in adult neural stem cells. J Cell Sci. 2015;128:3597-606 pubmed publisher
    ..We used mice with a hypomorphic mutation in DNA ligase IV (Lig4(Y288C)), ataxia telangiectasia mutated (Atm(-/-)) and double mutant Atm(-/-)/Lig4(Y288C) mice...
  33. Gu Y, Sekiguchi J, Gao Y, Dikkes P, Frank K, Ferguson D, et al. Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit-deficient mice. Proc Natl Acad Sci U S A. 2000;97:2668-73 pubmed
    ..DNA end joining employs Ku70, Ku80, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4, and DNA ligase IV (Lig4)...
  34. Gatz S, Ju L, Gruber R, Hoffmann E, Carr A, Wang Z, et al. Requirement for DNA ligase IV during embryonic neuronal development. J Neurosci. 2011;31:10088-100 pubmed publisher
    ..Ablation of DNA non-homologous end-joining (NHEJ) proteins, XRCC4 or DNA ligase IV (LigIV), confers ataxia telangiectasia mutated (ATM)-dependent apoptosis predominantly in the IZ...
  35. Buis J, Wu Y, Deng Y, Leddon J, Westfield G, Eckersdorff M, et al. Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation. Cell. 2008;135:85-96 pubmed publisher
    ..Therefore, nucleolytic processing by Mre11 is an essential function of fundamental importance in DNA repair, distinct from MRN control of ATM signaling. ..
  36. Wray J, Williamson E, Chester S, Farrington J, Sterk R, Weinstock D, et al. The transposase domain protein Metnase/SETMAR suppresses chromosomal translocations. Cancer Genet Cytogenet. 2010;200:184-90 pubmed publisher
    ..In primates, Metnase interacts with DNA Ligase IV (Lig IV) and promotes nonhomologous end-joining (NHEJ) DNA repair...
  37. Smogorzewska A, Karlseder J, Holtgreve Grez H, Jauch A, de Lange T. DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2. Curr Biol. 2002;12:1635-44 pubmed
    ..that telomere fusions resulting from inhibition of the telomere-protective factor TRF2 are generated by DNA ligase IV-dependent nonhomologous end joining (NHEJ)...
  38. Johnson N, Dillard M, Baluk P, McDonald D, Harvey N, Frase S, et al. Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity. Genes Dev. 2008;22:3282-91 pubmed publisher
    ..Therefore, LECs are one of the few differentiated cell types that require constant expression of a certain gene to maintain their phenotypic identity. ..
  39. Gostissa M, Yan C, Bianco J, Cogne M, Pinaud E, Alt F. Long-range oncogenic activation of Igh-c-myc translocations by the Igh 3' regulatory region. Nature. 2009;462:803-7 pubmed publisher
  40. Foster S, De S, Johnson L, Petrini J, Stracker T. Cell cycle- and DNA repair pathway-specific effects of apoptosis on tumor suppression. Proc Natl Acad Sci U S A. 2012;109:9953-8 pubmed publisher
    ..mutation in p53 (R172P), which selectively impairs its function in apoptosis, rescued the lethality of mice lacking Lig4, a ligase required for nonhomologous end-joining (NHEJ) repair of DNA double-strand breaks in G0/G1...
  41. Sharpless N, Ferguson D, O Hagan R, Castrillon D, Lee C, Farazi P, et al. Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications, and deletions. Mol Cell. 2001;8:1187-96 pubmed
    ..a tumor-prone mouse strain (ink4a/arf(-/-)), we examined the impact of haploinsufficiency of a NHEJ component, DNA ligase IV (Lig4), on murine tumorigenesis...
  42. Lee Y, Brown E, Chang S, McKinnon P. Pot1a prevents telomere dysfunction and ATM-dependent neuronal loss. J Neurosci. 2014;34:7836-44 pubmed publisher
    ..These data reveal that neural cell loss after DNA damage selectively engages Atm signaling, highlighting how specific DNA lesions can dictate neuropathology arising in human neurodegenerative syndromes. ..
  43. Lee Y, Miller H, Jensen P, Hernan R, Connelly M, Wetmore C, et al. A molecular fingerprint for medulloblastoma. Cancer Res. 2003;63:5428-37 pubmed
    ..In mice, Ptc1 haploinsufficiency and disruption of DNA repair (DNA ligase IV inactivation) or cell cycle regulation (Kip1, Ink4d, or Ink4c inactivation), in conjunction with p53 ..
  44. Konishi A, de Lange T. Cell cycle control of telomere protection and NHEJ revealed by a ts mutation in the DNA-binding domain of TRF2. Genes Dev. 2008;22:1221-30 pubmed publisher
    ..In contrast, the processing of dysfunctional telomeres by NHEJ occurred primarily in G1, being repressed in S/G2 in a cyclin-dependent kinase (CDK)-dependent manner. ..
  45. Tkáč J, Xu G, Adhikary H, Young J, Gallo D, Escribano Díaz C, et al. HELB Is a Feedback Inhibitor of DNA End Resection. Mol Cell. 2016;61:405-418 pubmed publisher
    ..We conclude that mammalian DNA end resection triggers its own inhibition via the recruitment of HELB. ..
  46. Dimitrova N, Chen Y, Spector D, de Lange T. 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility. Nature. 2008;456:524-8 pubmed publisher
  47. Gostissa M, Ranganath S, Bianco J, Alt F. Chromosomal location targets different MYC family gene members for oncogenic translocations. Proc Natl Acad Sci U S A. 2009;106:2265-70 pubmed publisher
    ..We have previously shown that mice deficient for the DNA Ligase4 (Lig4) nonhomologous DNA end-joining factor and the p53 tumor suppressor routinely develop progenitor (pro)-B cell ..
  48. Cortizas E, Zahn A, Hajjar M, Patenaude A, Di Noia J, Verdun R. Alternative end-joining and classical nonhomologous end-joining pathways repair different types of double-strand breaks during class-switch recombination. J Immunol. 2013;191:5751-63 pubmed publisher
  49. Huse J, Holland E. Genetically engineered mouse models of brain cancer and the promise of preclinical testing. Brain Pathol. 2009;19:132-43 pubmed publisher
    ..Examples showcasing the use of GEMMs in the testing of molecularly targeted therapeutics are given, and relevant topics, such as stem cell biology, in vivo imaging technology and radiotherapy, are also addressed. ..
  50. Zhou T, Hasty P, Walter C, Bishop A, Scott L, Rebel V. Myelodysplastic syndrome: an inability to appropriately respond to damaged DNA?. Exp Hematol. 2013;41:665-74 pubmed publisher
    ..Moreover, in view of our current understanding of how DNA damage response and repair pathways are affected by age in hematopoietic stem cells, we also explore how this might relate to MDS development. ..
  51. Kondo N, Takahashi A, Mori E, Ohnishi K, McKinnon P, Sakaki T, et al. DNA ligase IV as a new molecular target for temozolomide. Biochem Biophys Res Commun. 2009;387:656-60 pubmed publisher
    ..2 (XRCC2)and radiation sensitive mutant54 (Rad54), non-homologous end joining repair-related gene DNAligase IV (Lig4). Cell sensitivity to drug treatments was assessed using colony forming assays...
  52. Sfeir A, de Lange T. Removal of shelterin reveals the telomere end-protection problem. Science. 2012;336:593-7 pubmed publisher
  53. Helmink B, Tubbs A, Dorsett Y, Bednarski J, Walker L, Feng Z, et al. H2AX prevents CtIP-mediated DNA end resection and aberrant repair in G1-phase lymphocytes. Nature. 2011;469:245-9 pubmed publisher
    ..Thus, H2AX preserves the structural integrity of broken DNA ends in G1-phase lymphocytes, thereby preventing these DNA ends from accessing repair pathways that promote genomic instability. ..