Late embryonic lethality and impaired V (D)J recombination in mice lacking DNA ligase IV

Karen M. Frank, JoAnn M. Sekiguchi, Katherine J. Seidl, Wojciech Swat, Gary A. Rathbun, Hwei-Ling Cheng, Laurie Davidson, Landy Kangaloo and Frederick W. Alt ()
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Karen M. Frank: The Children's Hospital, Harvard University Medical School
JoAnn M. Sekiguchi: The Children's Hospital, Harvard University Medical School
Katherine J. Seidl: The Children's Hospital, Harvard University Medical School
Wojciech Swat: The Children's Hospital, Harvard University Medical School
Gary A. Rathbun: Harvard University Medical School
Hwei-Ling Cheng: The Children's Hospital, Harvard University Medical School
Laurie Davidson: The Children's Hospital, Harvard University Medical School
Landy Kangaloo: The Children's Hospital, Harvard University Medical School
Frederick W. Alt: The Children's Hospital, Harvard University Medical School

Nature, 1998, vol. 396, issue 6707, 173-177

Abstract: Abstract The DNA-end-joining reactions used for repair of double-strand breaks in DNA and for V (D)J recombination, the process by which immunoglobulin and T-cell antigen-receptor genes are assembled from multiple gene segments, use common factors. These factors include components of DNA-dependent protein kinase (DNA-PK), namely DNA-PKcs and the Ku heterodimer, Ku70–Ku80, and XRCC4 (ref. 1). The precise function of XRCC4 is unknown, but it interacts with DNA ligase IV. Ligase IV is one of the three known mammalian DNA ligases2; however, the in vivo functions of these ligases have not been determined unequivocally. Here we show that inactivation of the ligase IV gene in mice leads to late embryonic lethality. Lymphopoiesis in these mice is blocked and V (D)J joining does not occur. Ligase IV-deficient embryonic fibroblasts also show marked sensitivity to ionizing radiation, growth defects and premature senescence. All of these phenotypic characteristics, except embryonic lethality, resemble those associated with Ku70 and Ku80 deficiencies3,4,5,6, indicating that they may result from an impaired end-joining process that involves both Ku subunits and ligase IV. However, Ku-deficient mice are viable, so ligase IV must also be required for processes and/or in cell types in which Ku is dispensable.

Date: 1998
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DOI: 10.1038/24172

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