Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene

Abstract

Folate is essential for the de novo biosynthesis of purines and thymidylate, and is an important mediator in the transfer of methyl groups for DNA methylation. Folate deficiency, therefore, could contribute to abnormal DNA integrity and methylation patterns. We investigated the effect of isolated folate deficiency in rats on DNA methylation and DNA strand breaks both at the genomic level and within specific sequences of the p53 tumor suppressor gene. Our data indicate that folate deficiency induces DNA strand breaks and hypomethylation within the p53 gene. Such alterations either did not occur or were chronologically delayed when examined on a genome-wide basis, indicating some selectivity for the exons examined within the p53 gene. Folate insufficiency has been implicated in the development of several human and experimental cancers, and aberrations within these regions of the p53 gene that were examined in this study are thought to play an integral role in carcinogenesis. The aforementioned molecular alterations may therefore be a means by which dietary folate deficiency enhances carcinogenesis.

Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage

“…The data and analysis presented indicate that uracil misincorporation is a likely mechanism for folate-deficiency-induced cytogenetic damage, although other mechanisms, such as site-specific hypomethylation, could contribute (40,41). The findings are likely to be applicable to proliferating tissues in general and suggest that, in folate-deficient humans, increased folate intake may decrease the risk of many types of cancer (9-11).…”

Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines

“…In vitro [15][16][17][18] and in vivo [19][20][21] studies reveal that this nucleotide imbalance promotes the misincorporation of uracil into DNA and the subsequent formation of doublestranded DNA breaks (DSB) through the excision of closely spaced uracil residues on opposing strands during repair [22]. Low dietary folate intake promotes genomic strand breakage in the liver of rats [21,23,24] and micropigs [25]. In addition, folate-depletion-induced DNA breakage has been observed in primary human lymphocytes [17,26] and rodent cell lines [15,27] in vitro.…”

“…In addition to disturbing nucleotide metabolism, folate depletion is reported to cause genomic hypomethylation in humans [19] and in cell culture [29] and p53 gene-specific hypomethylation in rats [23,24]. Although a depletion of the universal methyl donor Sadenosylmethionine is observed during folate depletion, the accumulation of its precursor Sadenosylhomocysteine, an inhibitor of DNA methyltransferases, appears to be a stronger predictor of hypomethylation [30].…”

Folate Pathway Gene MTHFR C677T Polymorphism and Risk of Lung Cancer in Asian Populations

“…A less active form of MTHFR leads to lower S-adenosyl-Lmethionine levels and consequently to hypomethylation; this phenomenon would be expected to increase the risk of some cancers (Stern et al, 2000). Similarly, low folate intake may modify cancer risk by inducing uracil misincorporation during DNA synthesis, leading to chromosomal damage, DNA strand breaks and impaired DNA repair, and DNA hypomethylation (Blount et al, 1997;Kim et al, 1997;Duthie, 1999;Kim, 1999).…”