p53 Disruption Increases Uracil Accumulation in DNA of Murine Embryonic Fibroblasts and Leads to Folic Acid-Nonresponsive Neural Tube Defects in Mice.

BACKGROUND: Neural tube defects (NTDs) occur in nervous tissue during embryogenesis when the neural tube fails to close. Approximately 70% of all human NTDs can be prevented by folic acid (FA). Altered expression and/or function of the tumor suppressor protein p53 can lead to NTDs in mouse models. OBJECTIVES: The aim of this study was to determine if dietary FA could rescue p53-/--induced NTDs in mice, and to determine the effect loss of p53 has on pathways in folate 1-carbon metabolism. METHODS: p53+/- female mice were randomly allocated and weaned onto either an FA-sufficient diet (2 mg/kg folic acid; +FA), or an FA-deficient diet (-FA). After 8 wk, the females were time-mated to p53-/- males. Embryos were examined at E12.5 for NTDs. Folate enzyme concentrations, nucleotide synthesis, uracil accumulation in DNA, and proliferation were measured in primary murine embryonic fibroblasts (MEFs). The "n - 1" chi-square test was used to compare NTD percentages, whereas all other data were analyzed by Student t test, except where noted a multilevel-fit model was used. RESULTS: NTD rates of litters from dams consuming the +FA diet (20/46; 43%) did not differ from those of litters from dams consuming the -FA diet (14/35; 40%) (P > 0.05). p53-/- MEFs had 55% higher rates of folate-dependent de novo dTMP synthesis, a approximately 2-fold higher accumulation of uracil in DNA, and a approximately 30% higher rate of proliferation (P