LATE EMBRYONIC LETHALITY AND IMPAIRED V(D)J RECOMBINATION IN MICE LACKING DNA-LIGASE-IV

The DNA-end-joining reactions used for repair of double-strand breaks in DNA and for V(D)J recombination, the process by which immunoglobuli n and T-cell antigen-receptor genes are assembled from multiple gene s egments, use common factors. These factors include components of DNA-d ependent protein kinase (DNA-PK), namely DNA-PE;cs and the Ku heterodi mer, Ku70-Ku80, and XRCC4 (ref. 1). The precise function of XRCC4 is u nknown, but it interacts with DNA ligase IV. Ligase IV is one of the t hree known mammalian DNA ligases(2); however, the in vivo functions of these Ligases have not been determined unequivocally. Here we show th at inactivation of the ligase IV gene in mice leads to late embryonic lethality. Lymphopoiesis in these mice is blocked and V(D)I joining do es not occur. Ligase IV-deficient embryonic fibroblasts also show mark ed sensitivity to ionizing radiation, growth defects and premature sen escence. All of these phenotypic characteristics, except embryonic let hality, resemble those associated with Ku70 and Ku80 deficiencies(3-6) , indicating that they may result from an impaired end-joining process that involves both Ku subunits and ligase N. However, Ku-deficient mi ce are viable, so ligase TV must also be required for processes and/or in cell types in which Ku is dispensable.