Folic acid deficiency increases chromosomal instability, chromosome 21 aneuploidy and sensitivity to radiation-induced micronuclei

Cytokinesis-block micronucleus cytome assay

“…More recent studies indicate that this method is likely to also prove fruitful in the emerging fields of nutrigenomics and toxicogenomics and their combinations, as it becomes increasingly clear that nutrient status also impacts on sensitivity to exogenous genotoxins 59 . The ultimate test of the CBMN Cyt assay is its ability to predict disease outcomes prospectively.…”

Folate Deficiency Induces Neurodegeneration and Brain Dysfunction in Mice Lacking Uracil DNA Glycosylase

“…Under conditions of folate depletion, a block in the methylation of dUMP to TMP increases intracellular deoxyuridine triphosphate (dUTP) by several orders of magnitude while concomitantly deoxythymidine triphosphate (dTTP) levels drop (Goulian et al, 1980b). Furthermore, a deficiency in folate has been reported to lead to an increase in genome instability (Beetstra et al, 2005), possibly the result of uracil misincorporation into DNA in proliferating cells and the subsequent formation of A:U mismatches. In addition, spontaneous hydrolytic deamination of cytosine both in proliferating and in differentiated cells also results in erroneous uracil residues in the form of U:G mispairs (Barnes and Lindahl, 2004).…”

The effects of methyl-donor deficiency on mutation induction and transgenerational instability in mice

“…The term 'folate' encompasses all one-carbon substituted and glutamylated derivatives of folic acid (Christensen et al, 2011). Folic acid is folate's synthetic oxidized form and is used in fortified foods and vitamin supplements, since it is more stable (Beetstra et al, 2005). Folic acid is made up of three parts: a pteridine ring system (6-methylpterin), a paraaminobenzoic acid and a glutamic acid (Figure 1.…”

“…SAM is the most important methyl group donor for the majority of biological reactions such as DNA methylation, as well as methylation of lysine and arginine residues in histones (Chiang et al, 1996). SAM is therefore vital for the determination of gene expression and prevention of chromosomal breakage, particularly in regions like the centromeric and fragile sites (Eto et al, 1986;Beetstra et al, 2005). Additionally, methylation by SAM is essential for protein stabilization (e.g myelin) and is implicated in the synthesis of many molecules including melatonin, norepinephrine, and carnitine.…”

“…The 5-methylTHF is used in the one-carbon metabolism cycle by donating its methyl group to homocysteine, converting it to methionine (Eto et al, 1986;Beetstra et al, 2005) and by that, replenishing cellular SAM (Caudill et al, 2001;Fenech, 2001;Anderson et al, 2012). This favours the increase in the dUMP pool and promotes an even bigger uracil incorporation into DNA.…”