DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway

DNA ligase IV (LIG4) is a nonhomologous end-joining (NHEJ) protein used for V(D)J recombination and DNA repair. In mice, Lig4 deficiency causes embryo nic lethality, massive neuronal apoptosis, arrested lympho-genesis, and var ious cellular defects. Herein, we assess potential roles in this phenotype for INK4a/ARF and p53, two proteins implicated in apoptosis and senescence. INK4a/ARF deficiency rescued proliferation/senescence defects of Lig4-defi cient fibroblasts but not other phenotypic aspects. In contrast, p53 defici ency rescued embryonic lethality, neuronal apoptosis, and fibroblast prolif eration/senescence defects but not lymphocyte development or radiosensitivi ty. Young Lig4/p53 double null mice routinely died from pro-B lymphomas. Th us, in the context of Lig4 deficiency, embryonic lethality and neuronal apo ptosis likely result from a p53-dependent response to unrepaired DNA damage , and neuronal apoptosis and lymphocyte developmental defects can be mechan istically dissociated.