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

Abstract

<jats:title>ABSTRACT</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Objectives</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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 &amp;gt; 0.05). p53−/− MEFs had 55% higher rates of folate-dependent de novo dTMP synthesis, a ∼2-fold higher accumulation of uracil in DNA, and a ∼30% higher rate of proliferation (P ≤ 0.05) than p53+/− MEFs independent of folate.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>p53-related NTDs are not FA responsive. Increased dTMP synthesis in p53−/− MEFs might not have been sufficient to meet the demands for thymidine triphosphate (dTTP) synthesis as evidenced by the elevated amounts of uracil in DNA. This study provides additional evidence that elevated uracil in DNA is a risk factor for NTDs.</jats:p> </jats:sec>

Identification of potential key ferroptosis- and autophagy-related genes in myelomeningocele through bioinformatics analysis

“…Here, we observed that TFs such as P53, POU3F2, TATA and E4BP4 are involved in the regulation of candidate genes. P53 a transcription factor involved in the development of NTDs [ 52 , 53 ]. The p53 N236S mutation results in decreased neuroepithelial differentiation and apoptosis, increased neuroepithelial proliferation during neurulation, and failure of neural tube closure, leading to the development of NTDs [ 54 ].…”

A novel dual-prodrug carried by cyclodextrin inclusion complex for the targeting treatment of colon cancer

“…Folic acid (FA) is widely used in cancer treatment. Compared with other ligands, FA exhibits some advantages of high affinity for the receptor, obvious specificity, good coupling, low cost, and non-immunogenicity [29,30]. In this experiment, folic acid was used as a ligand to modify CM-β-CD, further improving the drug targeting, reducing the side effects of drugs, playing a better curative effect, and achieving the purpose of tumor suppression [31].…”

Folic Acid Alleviates High Glucose and Fat-Induced Pyroptosis via Inhibition of the Hippo Signal Pathway on H9C2 Cells

“…Folic acid (vitamin B9) is essential for DNA/RNA synthesis, and its deficiency is associated with a higher risk of neural tube defects, cancer and coronary heart disease (Z. Wang et al, 2018;Lachenauer et al, 2020;Jelicic et al, 2020). Previous studies have shown that the severity of diabetic retinopathy is inversely correlated to circulating folic acid levels (Malaguarnera et al, 2015).…”