p53 Deficiency Rescues Neuronal Apoptosis but Not Differentiation in DNA Polymerase β-Deficient Mice

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Abstract
In mammalian cells, DNA polymerase β (Polβ) functions in base excision repair. We have previously shown that Polβ-deficient mice exhibit extensive neuronal cell death (apoptosis) in the developing nervous system and that the mice die immediately after birth. Here, we studied potential roles in the phenotype for p53, which has been implicated in DNA damage sensing, cell cycle arrest, and apoptosis. We generated Polβ−/− p53−/− double-mutant mice and found that p53 deficiency dramatically rescued neuronal apoptosis associated with Polβ deficiency, indicating that p53 mediates the apoptotic process in the nervous system. Importantly, proliferation and early differentiation of neuronal progenitors in Polβ−/− p53−/− mice appeared normal, but their brains obviously displayed cytoarchitectural abnormalities; moreover, the mice, like Polβ−/− p53+/+ mice, failed to survive after birth. Thus, we strongly suggest a crucial role for Polβ in the differentiation of specific neuronal cell types.