DNA-DAMAGE IN FOLATE-DEFICIENCY

Folic acid deficiency breaks chromosomes and is associated with increased cancer risk in humans (Blount, 1994; Glynn and Albanes, 1994). Folate-deficient epithelial tissues are at increased risk of neoplastic transformation (Butterworth, 1993), probably due to the role that folate plays in DNA synthesis, repair and methylation (Krumdieck, 1983). Folate deficiency could cause increased risk of dancer by breaking chromosomes due to uracil misincorporation or by decreasing DNA methylation (Herbert, 1986). Uracil misincorporation/repair and hypomethylation are not mutually exclusive mechanisms and both could be important. The role of folate deficiency-induced hypomethylation in carcinogenesis has been reviewed recently (Mason, 1995). This chapter will focus on the potential role of uracil misincorporation and repair for inducing chromosome breaks and cancer. Uracil misincorporation into DNA and its subsequent excision repair is a plausible mechanism for folate deficiency-induced chromosome breaks in humans (Goulian et al, 1980b; Reidy, 1988; MacGregor et al, 1990; Wickramasinghe and Fida, 1994). Folate deficiency reduces thymidylate synthase-mediated methylation of deoxyuridylate to thymidylate (Matthews et al, 1990). The ensuing nucleotide imbalance increases the frequency of uracil misincorporation into DNA (Goulian et al, 1980b). Simultaneous removal and repair of two adjacent uracil residues on opposite strands can result in a double-strand DNA break (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 breaks as measured by micronucleated cells. A calculation is presented to explain how the levels of uracil misincorporation observed may cause chromosome breaks (Blount, 1994). Unrepaired double-strand DNA breaks decrease genetic stability and therefore increase cancer risk (Rosin and Ochs, 1986; Weinberg, 1988).