Genetic interactions between ATM and the nonhomologous end-joining factorsin genomic stability and development

DNA ligase IV (Lig4) and the DNA-dependent protein kinase (DNA-PK) function in nonhomologous end joining (NHEJ). However, although Lig4 deficiency cau ses late embryonic lethality, deficiency in DNA-PK subunits (Ku70, Ku80, an d DNA-PKcs) does not. Here we demonstrate that, similar to p53 deficiency, ataxia-telangiectasia-mutated (ATM) gene deficiency rescues the embryonic l ethality and neuronal apoptosis, but not impaired lymphocyte development, a ssociated with Lig4 deficiency. However, in contrast to p53 deficiency, ATM deficiency enhances deleterious effects of Lig4 deficiency on growth poten tial of embryonic fibroblasts (MEFs) and genomic instability in both MEFs a nd cultured progenitor lymphocytes, demonstrating significant differences i n the interplay of p53 vs. ATM with respect to NHEJ. Finally, in dramatic c ontrast to effects on Lig4 deficiency, ATM deficiency causes early embryoni c lethality in Ku- or DNA-PKcs-deficient mice, providing evidence for an NH EJ-independent role for the DNA-PK holoenzyme.