title: Folate depletion in human lymphocytes up-regulates p53 expression despite marked induction of strand breaks in exons 5-8 of the gene.
abstract: Low dietary folate intake is associated with an elevated risk for carcinogenesis. One putative mechanism by which folate depletion promotes carcinogenesis is by inducing gene-specific strand breakage and impaired expression of affected genes. Primary human lymphocytes were cultured in media containing 15, 30 or 120 nM folic acid. p53 strand breaks, gene and protein expression, and p21 transcript were determined. Cells grown in 15 nM folate developed significant levels of p53 strand breaks, reflected by reductions in amplifiable DNA from p53 exons 5-8 (approximately 40% loss, P<0.0001) and exons 7-8 (approximately 26% loss, P<0.0001) compared to 30 and 120 nM. Nevertheless, steady-state p53 transcript was elevated two-fold in 15 and 30 compared to 120 nM (P<0.001). p53 protein abundance increased with decreasing media folate, as did p21 transcript. The cytokinesis-block micronucleus assay demonstrated a three-fold increase in chromosomal damage at the two lower folate concentrations (P<0.01). In primary human lymphocytes, folate depletion induces a marked increase in p53 exons 5-8 breaks, but does not reduce steady-state levels of p53 mRNA, protein, or impair downstream signaling. The induction of p53 strand breaks by folate depletion does not impair p53 expression or action within all human cell lines.
authors.affiliation: Vitamins and Carcinogenesis Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, United States. jimmy.crott@tufts.edu
authors.forename: Jimmy W
authors.initials: JW
authors.lastname: Crott
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Liu
authors.forename: Sang-Woon
authors.initials: SW
authors.lastname: Choi
authors.forename: Joel B
authors.initials: JB
authors.lastname: Mason
mesh_terms: D001483:Base Sequence; D017931:DNA Primers; D005091:Exons; D005494:Folic Acid Deficiency / Q000097:blood*; D016158:Genes, p53; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger