DNA-DAMAGE IN FOLATE-DEFICIENCY

Folic acid deficiency breaks chromosomes and is associated with increa sed cancer risk in humans (Blount, 1994; Glynn and Albanes, 1994). Fol ate-deficient epithelial tissues are at increased risk of neoplastic t ransformation (Butterworth, 1993), probably due to the role that folat e plays in DNA synthesis, repair and methylation (Krumdieck, 1983). Fo late deficiency could cause increased risk of dancer by breaking chrom osomes due to uracil misincorporation or by decreasing DNA methylation (Herbert, 1986). Uracil misincorporation/repair and hypomethylation a re not mutually exclusive mechanisms and both could be important. The role of folate deficiency-induced hypomethylation in carcinogenesis ha s been reviewed recently (Mason, 1995). This chapter will focus on the potential role of uracil misincorporation and repair for inducing chr omosome breaks and cancer. Uracil misincorporation into DNA and its su bsequent excision repair is a plausible mechanism for folate deficienc y-induced chromosome breaks in humans (Goulian et al, 1980b; Reidy, 19 88; MacGregor et al, 1990; Wickramasinghe and Fida, 1994). Folate defi ciency reduces thymidylate synthase-mediated methylation of deoxyuridy late to thymidylate (Matthews et al, 1990). The ensuing nucleotide imb alance increases the frequency of uracil misincorporation into DNA (Go ulian et al, 1980b). Simultaneous removal and repair of two adjacent u racil residues on opposite strands can result in a double-strand DNA b reak (Dianov et al, 1991) and decreased genetic stability (Figure 1). Results reviewed here indicate that folate deficiency in humans causes uracil misincorporation and significant increases in chromosome break s as measured by micronucleated cells. A calculation is presented to e xplain how the levels of uracil misincorporation observed may cause ch romosome breaks (Blount, 1994). Unrepaired double-strand DNA breaks de crease genetic stability and therefore increase cancer risk (Rosin and Ochs, 1986; Weinberg, 1988).