Xrcc4

Summary

Gene Symbol: Xrcc4
Description: X-ray repair complementing defective repair in Chinese hamster cells 4
Alias: 2310057B22Rik, AW413319, AW545101, DNA repair protein XRCC4, X-ray repair cross-complementing protein 4
Species: mouse
Products:     Xrcc4

Top Publications

  1. Wang J, Gostissa M, Yan C, Goff P, Hickernell T, Hansen E, et al. Mechanisms promoting translocations in editing and switching peripheral B cells. Nature. 2009;460:231-6 pubmed publisher
    ..Our studies show peripheral B cells that attempt secondary V(D)J recombination, and determine a role for mechanistic factors in promoting recurrent translocations in tumours...
  2. Soulas Sprauel P, Le Guyader G, Rivera Munoz P, Abramowski V, Olivier Martin C, Goujet Zalc C, et al. Role for DNA repair factor XRCC4 in immunoglobulin class switch recombination. J Exp Med. 2007;204:1717-27 pubmed
    ..Although the DNA repair factor XRCC4 is essential for the resolution of DNA DSB during V(D)J recombination, its role in CSR has not been established...
  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
    ..by classical nonhomologous end-joining (C-NHEJ), which employs the Ku70/80 complex for DSB recognition and XRCC4/DNA ligase 4 for ligation...
  4. Mori M, Itsukaichi H, Nakamura A, Sato K. Molecular characterization of ionizing radiation-hypersensitive mutant M10 cells. Mutat Res. 2001;487:85-92 pubmed
    ..In the present study, sequence analysis of Xrcc4 cDNA in M10 cells disclosed a transversion of A (370) to T, which results in a change of arginine (124) to a ..
  5. Li Z, Otevrel T, Gao Y, Cheng H, Seed B, Stamato T, et al. The XRCC4 gene encodes a novel protein involved in DNA double-strand break repair and V(D)J recombination. Cell. 1995;83:1079-89 pubmed
    ..On this basis, we isolated a human cDNA sequence, termed XRCC4, whose expression confers normal V(D)J recombination ability and significant restoration of DSBR activity to XR-1, ..
  6. Wang J, Alt F, Gostissa M, Datta A, Murphy M, Alimzhanov M, et al. Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching. J Exp Med. 2008;205:3079-90 pubmed publisher
    ..We now show that CD21-cre-mediated deletion of the Xrcc4 NHEJ gene in p53-deficient peripheral B cells leads to recurrent surface Ig-negative B lymphomas ("CXP ..
  7. 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 ..
  8. Xie A, Kwok A, Scully R. Role of mammalian Mre11 in classical and alternative nonhomologous end joining. Nat Struct Mol Biol. 2009;16:814-8 pubmed publisher
    ..Here we show that Mre11 promotes efficient NHEJ in both wild-type and Xrcc4(-/-) mouse embryonic stem cells...
  9. Wang Y, Nnakwe C, Lane W, Modesti M, Frank K. Phosphorylation and regulation of DNA ligase IV stability by DNA-dependent protein kinase. J Biol Chem. 2004;279:37282-90 pubmed
    DNA ligase IV (Lig4), x-ray cross-complementation group 4 (XRCC4), and DNA-dependent protein kinase (DNA-PK) are essential mammalian nonhomologous end joining proteins used for V(D)J recombination and DNA repair...

More Information

Publications52

  1. Kamdar R, Matsumoto Y. Radiation-induced XRCC4 association with chromatin DNA analyzed by biochemical fractionation. J Radiat Res. 2010;51:303-13 pubmed
    b>XRCC4, in association with DNA ligase IV, is thought to play a critical role in the ligation of two DNA ends in DNA double-strand break (DSB) repair through non-homologous end-joining (NHEJ) pathway...
  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
    ..The enzyme occurs in a complex with the XRCC4 gene product [3], an interaction mediated via its unique carboxyl terminus [4] [5]...
  3. Zha S, Alt F, Cheng H, Brush J, Li G. Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficient murine ES cells. Proc Natl Acad Sci U S A. 2007;104:4518-23 pubmed
    ..We conclude that, in mice, Cernunnos-XLF is essential for normal NHEJ-mediated repair of DNA DSBs and that Cernunnos-XLF acts as a genomic caretaker to prevent genomic instability. ..
  4. 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
    ..components of DNA-dependent protein kinase (DNA-PK), namely DNA-PKcs and the Ku heterodimer, Ku70-Ku80, and XRCC4. The precise function of XRCC4 is unknown, but it interacts with DNA ligase IV...
  5. 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. ..
  6. Gao Y, Ferguson D, Xie W, Manis J, Sekiguchi J, Frank K, et al. Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature. 2000;404:897-900 pubmed
    b>XRCC4 is a non-homologous end-joining protein employed in DNA double strand break repair and in V(D)J recombination...
  7. Guirouilh Barbat J, Rass E, Plo I, Bertrand P, Lopez B. Defects in XRCC4 and KU80 differentially affect the joining of distal nonhomologous ends. Proc Natl Acad Sci U S A. 2007;104:20902-7 pubmed
    b>XRCC4-null mice have a more severe phenotype than KU80-null mice. Here, we address whether this difference in phenotype is connected to nonhomologous end-joining (NHEJ)...
  8. Yan C, Kaushal D, Murphy M, Zhang Y, Datta A, Chen C, et al. XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice. Proc Natl Acad Sci U S A. 2006;103:7378-83 pubmed
    Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line leads to embryonic lethality, in association with apoptosis of newly generated, postmitotic neurons...
  9. 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
    b>XRCC4 was identified via a complementation cloning method that employed an ionizing radiation (IR)-sensitive hamster cell line...
  10. 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. ..
  11. 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
    ..nonhomologous DNA end joining employs Ku70, Ku80, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4, and DNA ligase IV (Lig4)...
  12. 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
    ..C-NHEJ) 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...
  13. Jiang W, Crowe J, Liu X, Nakajima S, Wang Y, Li C, et al. Differential phosphorylation of DNA-PKcs regulates the interplay between end-processing and end-ligation during nonhomologous end-joining. Mol Cell. 2015;58:172-85 pubmed publisher
    ..Together, our findings identify DNA-PKcs as the molecular switch that coordinates end-processing and end-ligation at the DNA ends through differential phosphorylations. ..
  14. Pierce A, Hu P, Han M, Ellis N, Jasin M. Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev. 2001;15:3237-42 pubmed
    ..We find that the HDR frequency is enhanced in Ku70(-/-), XRCC4(-/-), and DNA-PKcs(-/-) cells, with the increase being particularly striking in Ku70(-/-) cells...
  15. Imamichi S, Sharma M, Kamdar R, Fukuchi M, Matsumoto Y. Ionizing radiation-induced XRCC4 phosphorylation is mediated through ATM in addition to DNA-PK. Proc Jpn Acad Ser B Phys Biol Sci. 2014;90:365-72 pubmed
    b>XRCC4 (X-ray cross-complementation group 4) is a protein associated with DNA ligase IV, which is thought to join two DNA ends at the final step of DNA double-strand break repair through non-homologous end-joining...
  16. Fukuchi M, Wanotayan R, Liu S, Imamichi S, Sharma M, Matsumoto Y. Lysine 271 but not lysine 210 of XRCC4 is required for the nuclear localization of XRCC4 and DNA ligase IV. Biochem Biophys Res Commun. 2015;461:687-94 pubmed publisher
    b>XRCC4 and DNA Ligase IV (LIG4) cooperate to join two DNA ends at the final step of DNA double-strand break (DSB) repair through non-homologous end-joining (NHEJ)...
  17. 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
  18. 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
    ..the interaction between two key components of the NHEJ machinery, the Ku heterodimer and the DNA ligase IV/Xrcc4 complex...
  19. Kang Y, Balter B, Csizmadia E, Haas B, Sharma H, Bronson R, et al. Contribution of classical end-joining to PTEN inactivation in p53-mediated glioblastoma formation and drug-resistant survival. Nat Commun. 2017;8:14013 pubmed publisher
    ..Here we demonstrate that combined inactivation of the XRCC4 non-homologous end-joining (NHEJ) DNA repair gene and p53 efficiently induces brain tumours with hallmark ..
  20. 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. ..
  21. Chao C, Herr D, Chun J, Xu Y. Ser18 and 23 phosphorylation is required for p53-dependent apoptosis and tumor suppression. EMBO J. 2006;25:2615-22 pubmed
    ..In addition, p53S18/23A, but not p53S18A, could completely rescue embryonic lethality of Xrcc4(-/-) mice that is caused by massive p53-dependent neuronal apoptosis...
  22. Bhargava R, Carson C, Lee G, Stark J. Contribution of canonical nonhomologous end joining to chromosomal rearrangements is enhanced by ATM kinase deficiency. Proc Natl Acad Sci U S A. 2017;114:728-733 pubmed publisher
    ..We suggest that the contribution of the C-NHEJ pathway to the formation of a 0.4-Mbp deletion rearrangement is enhanced in ATM-deficient cells. ..
  23. d Adda di Fagagna F, Hande M, Tong W, Roth D, Lansdorp P, Wang Z, et al. Effects of DNA nonhomologous end-joining factors on telomere length and chromosomal stability in mammalian cells. Curr Biol. 2001;11:1192-6 pubmed
    ..By contrast, telomere length is not altered in cells impaired in XRCC4 or DNA ligase IV, two other NHEJ components...
  24. Eccleston J, Yan C, Yuan K, Alt F, Selsing E. Mismatch repair proteins MSH2, MLH1, and EXO1 are important for class-switch recombination events occurring in B cells that lack nonhomologous end joining. J Immunol. 2011;186:2336-43 pubmed publisher
    ..collectively or differentially influence the A-EJ mechanism of CSR by analyzing CSR in mice deficient in both XRCC4 and individual MMR proteins...
  25. Malivert L, Callebaut I, Rivera Munoz P, Fischer A, Mornon J, Revy P, et al. The C-terminal domain of Cernunnos/XLF is dispensable for DNA repair in vivo. Mol Cell Biol. 2009;29:1116-22 pubmed publisher
    The core nonhomologous end-joining DNA repair pathway is composed of seven factors: Ku70, Ku80, DNA-PKcs, Artemis, XRCC4 (X4), DNA ligase IV (L4), and Cernunnos/XLF (Cernunnos)...
  26. Oksenych V, Kumar V, Liu X, Guo C, Schwer B, Zha S, et al. Functional redundancy between the XLF and DNA-PKcs DNA repair factors in V(D)J recombination and nonhomologous DNA end joining. Proc Natl Acad Sci U S A. 2013;110:2234-9 pubmed publisher
    ..The XRCC4-like factor (XLF) is a C-NHEJ component that is not required for C-NHEJ of chromosomal signal joins or coding ..
  27. 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...
  28. Laulier C, Cheng A, Stark J. The relative efficiency of homology-directed repair has distinct effects on proper anaphase chromosome separation. Nucleic Acids Res. 2011;39:5935-44 pubmed publisher
  29. Lamparter C, Winn L. Tissue-specific effects of valproic acid on DNA repair genes and apoptosis in postimplantation mouse embryos. Toxicol Sci. 2014;141:59-67 pubmed publisher
    ..Quantitative PCR was used to measure the tissue-specific expression of lacZ, a surrogate measure of recombination, Xrcc4, Rad51, Brca1, and Brca2, with Western blotting used to quantify Rad51, cleaved caspase-3 and cleaved-PARP protein...
  30. Feng L, Hollstein M, Xu Y. Ser46 phosphorylation regulates p53-dependent apoptosis and replicative senescence. Cell Cycle. 2006;5:2812-9 pubmed
    ..In addition, p53hki(S46A) MEFs more readily escapes from Ras-induced senescence. Therefore, Ser46 phosphorylation activates p53-dependent apoptosis induced by DNA damage and cellular senescence induced by oncogenic stress. ..
  31. Weinstock D, Jasin M. Alternative pathways for the repair of RAG-induced DNA breaks. Mol Cell Biol. 2006;26:131-9 pubmed
    ..As expected, V(D)J recombination was substantially impaired in cells deficient for the NHEJ components Ku70, XRCC4, and DNA-PKcs...
  32. Rucci F, Notarangelo L, Fazeli A, Patrizi L, Hickernell T, Paganini T, et al. 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. 2010;107:3024-9 pubmed publisher
    ..These findings highlight the importance of LIG4 in lymphocyte development and function, and in genomic stability maintenance, and provide a model for the complex phenotype of LIG4 syndrome in humans. ..
  33. Schulte Uentrop L, El Awady R, Schliecker L, Willers H, Dahm Daphi J. Distinct roles of XRCC4 and Ku80 in non-homologous end-joining of endonuclease- and ionizing radiation-induced DNA double-strand breaks. Nucleic Acids Res. 2008;36:2561-9 pubmed publisher
    ..of DNA double-strand breaks (DSBs) is mediated by two protein complexes comprising Ku80/Ku70/DNA-PKcs/Artemis and XRCC4/LigaseIV/XLF...
  34. Zhu X, Niedernhofer L, Kuster B, Mann M, Hoeijmakers J, de Lange T. ERCC1/XPF removes the 3' overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes. Mol Cell. 2003;12:1489-98 pubmed
  35. Arlt M, Rajendran S, Birkeland S, Wilson T, Glover T. De novo CNV formation in mouse embryonic stem cells occurs in the absence of Xrcc4-dependent nonhomologous end joining. PLoS Genet. 2012;8:e1002981 pubmed publisher
    ..repair is involved in the formation of this class of CNVs, chromosome integrity was monitored in NHEJ-deficient Xrcc4(-/-) mouse embryonic stem (ES) cells following treatment with low doses of aphidicolin, a DNA replicative ..
  36. Wanotayan R, Fukuchi M, Imamichi S, Sharma M, Matsumoto Y. Asparagine 326 in the extremely C-terminal region of XRCC4 is essential for the cell survival after irradiation. Biochem Biophys Res Commun. 2015;457:526-31 pubmed publisher
    b>XRCC4 is one of the crucial proteins in the repair of DNA double-strand break (DSB) through non-homologous end-joining (NHEJ)...
  37. Pieraccioli M, Nicolai S, Antonov A, Somers J, Malewicz M, Melino G, et al. ZNF281 contributes to the DNA damage response by controlling the expression of XRCC2 and XRCC4. Oncogene. 2016;35:2592-601 pubmed publisher
    ..In line with this finding, XRCC2 and XRCC4, two genes that take part in homologous recombination and non-homologous end joining, respectively, were ..
  38. Chen Z, Elos M, Viboolsittiseri S, Gowan K, Leach S, Rice M, et al. Combined deletion of Xrcc4 and Trp53 in mouse germinal center B cells leads to novel B cell lymphomas with clonal heterogeneity. J Hematol Oncol. 2016;9:2 pubmed publisher
    ..In the current study, we establish a unique mouse model by specifically deleting a NHEJ gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in GC B cells, which results in the spontaneous development of B cell ..
  39. Zhang Q, Karnak D, Tan M, Lawrence T, Morgan M, Sun Y. FBXW7 Facilitates Nonhomologous End-Joining via K63-Linked Polyubiquitylation of XRCC4. Mol Cell. 2016;61:419-433 pubmed publisher
    ..FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7...
  40. Gompers A, Su Feher L, Ellegood J, Copping N, Riyadh M, Stradleigh T, et al. Germline Chd8 haploinsufficiency alters brain development in mouse. Nat Neurosci. 2017;20:1062-1073 pubmed publisher
    ..This integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development. ..
  41. Yamano M, Tohyama M. Distribution of corticotropin-releasing factor and calcitonin gene-related peptide in the developing mouse cerebellum. Neurosci Res. 1994;19:387-96 pubmed
    ..Furthermore, CRF-IR fibers gradually changed to become typical climbing fibers, while CGRP-IR disappeared altogether. ..
  42. Chen Z, Gowan K, Leach S, Viboolsittiseri S, Mishra A, Kadoishi T, et al. Unexpected effects of different genetic backgrounds on identification of genomic rearrangements via whole-genome next generation sequencing. BMC Genomics. 2016;17:823 pubmed
    ..established a unique mouse model by specifically deleting a key non-homologous end-joining DNA repair gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in germinal center B cells...
  43. Hartlerode A, Willis N, Rajendran A, Manis J, Scully R. Complex Breakpoints and Template Switching Associated with Non-canonical Termination of Homologous Recombination in Mammalian Cells. PLoS Genet. 2016;12:e1006410 pubmed publisher
    ..find that non-canonical HR termination can occur in the absence of the classical non-homologous end joining gene XRCC4. We observe obligatory use of microhomology (MH)-mediated end joining and/or nucleotide addition during rejoining ..